Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same

ABSTRACT

Provided are a novel compound having an antagonistic activity for the P2X 7  receptor, and a pharmaceutical composition having an antagonistic activity for the P2X 7  receptor. The compound represented by Formula (I): 
                         
wherein the symbols are defined in the specification, or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The invention relates to a compound useful for the treatment of diseasesor conditions associated with the P2X₇ receptor and a pharmaceuticalcomposition containing thereof.

BACKGROUND ART

Adenosine triphosphate (ATP) is known to serve as a source of energy incells and a substrate of phosphorylation, as well as an extracellularmessenger. It is known that ATP is released from a cell by variousstimulation such as cellular injury, inflammation, nociceptive stimulus,reduced blood oxygen level, and also known to be released together withanother messenger from a primary sensory nerve terminal. (Non-PatentDocument 1) ATP thus released mediates various extracellular signaltransductions through an ATP receptor.

ATP receptor is categorized into ionotropic P2X family and Gprotein-coupled P2Y family. For P2X family, seven subtypes have beenreported, and a member of this family forms a homo-trimeric structure ora hetero-trimeric structure together with another member of this subtypeand functions as a non-specific cation channel.

The P2X₇ receptor, a non-selective cation channel, belongs to the P2Xfamily, and forms a homo-trimeric structure. Activation of P2X₇ byextracellular ATP allows for the passage of cations across the plasmamembrane. Prolonged or repeated ATP stimulation leads to the poreformation of pannexin hemichannel, and induces the cellular activationfollowing the release of small molecule such as ATP. (Non-PatentDocument 2) It is reported that the activation of P2X₇ is involved ininflammation, immune and pain by the maturation and secretion ofproinflammatory cytokines such as interleukin-1 beta and interleukin-18.(Non-Patent Document 3) Thus, it is known that the P2X₇ receptor isinvolved in pain, central nervous system disease, immune disease andinflammatory disease. (Non-Patent Document 7-8, and Patent Document 1)

P2X₇ is distributed in macrophages, mast cells, microglia, andastrocytes. It is known that disruption of the P2X₇ receptor geneabolishes chronic inflammatory and neuropathic pain. (Non-PatentDocument 4) It is reported that the P451L mutation of the mouse P2X₇gene has impaired pore formation and shows less mechanical sensitivityof neuropathic pain model mice. (Non-Patent Document 5) Additionally, anassociation between lower pain intensity in chronic pain patients andthe hypofunctional allele of P2X₇ has been reported, suggesting thatP2X₇ antagonist is useful in the treatment of chronic pain such asrheumatoid arthritis, osteoarthritis and neuropathic pain.

Additionally, it has been reported that P2X₇ may be involved in multiplesclerosis, spinal cord injury, stroke, Alzheimer's disease, anddepression (Non-Patent Document 6), suggesting that P2X₇ antagonist isuseful in the treatment of these central nervous system disease.

The compounds having an analgesic effect are described in PatentDocuments 2 and 3. However, the compounds have different chemicalstructures from the compounds of the present invention, and there isneither disclosure nor suggestion about an antagonistic activity for theP2X₇ receptor.

The compounds having an antagonistic activity for the P2X₇ receptor aredescribed in Patent Documents 4 and 5. However, the compounds havedifferent chemical structures from the compounds of the presentinvention.

PRIOR ART REFERENCES Patent Document

-   [Patent Document 1] International Publication WO 2012/036193A-   [Patent Document 2] International Publication WO 2013/118855A-   [Patent Document 3] International Publication WO 2012/020742A-   [Patent Document 4] International Publication WO 2015/099107A-   [Patent Document 5] International Publication WO 2016/171249A

Non-patent Document

-   [Non-patent Document 1] Burnstock G., Mol Pain. 2009. 5. 69-   [Non-patent Document 2] Baroja-Mazo A et al., Biochim Biophys    Acta. 2013. 1828. 79-93-   [Non-patent Document 3] MacKenzie A et al., Immunity. 2001. 15.    825-835-   [Non-patent Document 4] Chessell I P et al., Pain. 2005. 114.    386-396-   [Non-patent Document 5] Sorge R E et al., Nature Med. 2012. 18.    595-599-   [Non-patent Document 6] Skaper S D et al., FASEB J. 2010. 24.    337-345-   [Non-patent Document 7] Takenouchi T et al., Arch Immunol Ther Exp    (Warsz). 2010 April; 58(2): 91-6-   [Non-patent Document 8] Friedle S A et al., Recent Pat CNS Drug    Discov. 2010 January; 5(1): 35-45

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The objective of the present invention is to provide novel compoundshaving an antagonistic activity for the P2X₇ receptor and apharmaceutical composition having an antagonistic activity for the P2X₇receptor.

Means for Solving the Problem

The present invention relates to the following (1′), (1) to (44) and(1001) to (1007):

-   (1″)

A compound represented by Formula (I):

wherein

Z¹ is C(R⁴) or N;

R⁴ is a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, or substituted or unsubstituted alkynylamino;

Z² is C(R^(5a))(R^(5a′)) or N(R^(5b));

the dashed line represents the presence or absence of a bond;

when the dashed line represents the presence of a bond, then R^(5a′) andR^(5b) are absent;

R^(5a) and R^(5a′) are each independently a hydrogen atom, halogen,hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino,substituted or unsubstituted alkenylamino, substituted or unsubstitutedalkynylamino, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy,substituted or unsubstituted alkenylcarbonyloxy, substituted orunsubstituted alkynylcarbonyloxy, substituted or unsubstitutedalkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted alkylsulfonyloxy, substituted or unsubstitutedalkenylsulfonyloxy, substituted or unsubstituted alkynylsulfonyloxy,substituted or unsubstituted alkyloxysulfonyl, substituted orunsubstituted alkenyloxysulfonyl, substituted or unsubstitutedalkynyloxysulfonyl, substituted or unsubstituted alkylcarbamoyl,substituted or unsubstituted alkenylcarbamoyl, substituted orunsubstituted alkynylcarbamoyl, substituted or unsubstitutedalkylsulfamoyl, substituted or unsubstituted alkenylsulfamoyl,substituted or unsubstituted alkynylsulfamoyl, substituted orunsubstituted alkylcarbonylamino, substituted or unsubstitutedalkenylcarbonylamino, substituted or unsubstituted alkynylcarbonylamino,substituted or unsubstituted alkylsulfonylamino, substituted orunsubstituted alkenylsulfonylamino, substituted or unsubstitutedalkynylsulfonylamino, substituted or unsubstitutedalkyloxycarbonylamino, substituted or unsubstitutedalkenyloxycarbonylamino, substituted or unsubstitutedalkynyloxycarbonylamino, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylamino, substituted or unsubstitutednon-aromatic carbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

R^(5b) is a hydrogen atom, carboxy, carbamoyl, sulfamoyl, sulfo, cyano,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylcarbamoyl,substituted or unsubstituted alkenylcarbamoyl, substituted orunsubstituted alkynylcarbamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, or substituted or unsubstituted non-aromaticheterocyclylcarbamoyl;

Ring Q is a substituted or unsubstituted 5-membered non-aromaticheterocycle or a substituted or unsubstituted 6-membered non-aromaticheterocycle;

Y¹ is N(R⁶), O, or S;

R⁶ is a hydrogen atom, hydroxy, cyano, carboxy, carbamoyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, or substituted orunsubstituted non-aromatic heterocyclyl;

R^(2a) is a group represented by the formula: (C(R^(2a′))(R^(2b′)))_(n)—R¹;

R^(2b) is a hydrogen atom, halogen, hydroxy, substituted orunsubstituted alkyl, or substituted or unsubstituted alkyloxy;

R^(2a′) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2b′) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2a′) and R^(2b′) which are attached to the same carbon atom may betaken together to form oxo;

R¹ is substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

X is N(R^(7a)), C(R^(8a))(R^(8b)), O or S;

R^(7a) is a hydrogen atom, substituted or unsubstituted alkyl, orsubstituted or unsubstituted alkylcarbonyl;

R^(8a) and R^(8b) are each independently a hydrogen atom, halogen,hydroxy, substituted or unsubstituted alkyl, or substituted orunsubstituted alkyloxy;

R^(2c) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2d) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2c) and R^(2d) which are attached to the same carbon atom may betaken together to form a substituted or unsubstituted non-aromaticcarbocycle, or two R^(2c) may be taken together to form a substituted orunsubstituted non-aromatic carbocycle;

R³ is substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

n is an integer from 0 to 4; and

m is an integer from 0 to 4,

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.

(1′) A compound represented by Formula (I):

wherein

Z¹ is C(R⁴) or N;

R⁴ is a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, or substituted or unsubstituted alkynylamino;

Z² is C(R^(5a))(R^(5a)) or N(R^(5b));

the dashed line represents the presence or absence of a bond;

when the dashed line represents the presence of a bond, then R^(5a′) andR^(5b) are absent;

R^(5a) and R^(5a′) are each independently a hydrogen atom, halogen,hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino,substituted or unsubstituted alkenylamino, substituted or unsubstitutedalkynylamino, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy,substituted or unsubstituted alkenylcarbonyloxy, substituted orunsubstituted alkynylcarbonyloxy, substituted or unsubstitutedalkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted alkylsulfonyloxy, substituted or unsubstitutedalkenylsulfonyloxy, substituted or unsubstituted alkynylsulfonyloxy,substituted or unsubstituted alkyloxysulfonyl, substituted orunsubstituted alkenyloxysulfonyl, substituted or unsubstitutedalkynyloxysulfonyl, substituted or unsubstituted alkylcarbamoyl,substituted or unsubstituted alkenylcarbamoyl, substituted orunsubstituted alkynylcarbamoyl, substituted or unsubstitutedalkylsulfamoyl, substituted or unsubstituted alkenylsulfamoyl,substituted or unsubstituted alkynylsulfamoyl, substituted orunsubstituted alkylcarbonylamino, substituted or unsubstitutedalkenylcarbonylamino, substituted or unsubstituted alkynylcarbonylamino,substituted or unsubstituted alkylsulfonylamino, substituted orunsubstituted alkenylsulfonylamino, substituted or unsubstitutedalkynylsulfonylamino, substituted or unsubstitutedalkyloxycarbonylamino, substituted or unsubstitutedalkenyloxycarbonylamino, substituted or unsubstitutedalkynyloxycarbonylamino, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylamino, substituted or unsubstitutednon-aromatic carbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

R^(5b) is a hydrogen atom, carboxy, carbamoyl, sulfamoyl, sulfo, cyano,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylcarbamoyl,substituted or unsubstituted alkenylcarbamoyl, substituted orunsubstituted alkynylcarbamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, or substituted or unsubstituted non-aromaticheterocyclylcarbamoyl;

Ring Q is a substituted or unsubstituted 5-membered non-aromaticheterocycle, a substituted or unsubstituted 5-membered aromaticheterocycle, or a substituted or unsubstituted 6-membered non-aromaticheterocycle;

Y¹ is N(R⁶), O, or S;

R⁶ is a hydrogen atom, hydroxy, cyano, carboxy, carbamoyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, or substituted orunsubstituted non-aromatic heterocyclyl;

R^(2a) is a group represented by the formula:—(C(R^(2a′))(R^(2b′)))^(n)—R¹;

R^(2b) is a hydrogen atom, halogen, hydroxy, substituted orunsubstituted alkyl, or substituted or unsubstituted alkyloxy;

R^(2a′) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2b′) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2a′) and R^(2b′) which are attached to the same carbon atom may betaken together to form oxo;

R¹ is substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

X is N(R^(7a)), C(R^(8a))(R^(8b)), O or S;

R^(7a) is a hydrogen atom, substituted or unsubstituted alkyl, orsubstituted or unsubstituted alkylcarbonyl;

R^(8a) and R^(8b) are each independently a hydrogen atom, halogen,hydroxy, substituted or unsubstituted alkyl, or substituted orunsubstituted alkyloxy;

R^(2c) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2d) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2c) and R^(2d) which are attached to the same carbon atom may betaken together to form a substituted or unsubstituted non-aromaticcarbocycle, or two R^(2c) may be taken together to form a substituted orunsubstituted non-aromatic carbocycle;

R³ is substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, or substituted or unsubstituted non-aromaticcarbocyclyl;

n is an integer from 0 to 4; and

m is an integer from 0 to 4,

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.

-   (1)

A compound represented by Formula (I):

wherein

Z¹ is C(R⁴) or N;

R⁴ is a hydrogen atom, halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, or substituted or unsubstituted alkynylamino;

Z² is C(R^(5a))(R^(5a′)) or N(R^(5b));

the dashed line represents the presence or absence of a bond;

when the dashed line represents the presence of a bond, then R^(5a′) andR^(5b) are absent;

R^(5a) and R^(5a′) are each independently a hydrogen atom, halogen,hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl,substituted or unsubstituted alkenylsulfanyl, substituted orunsubstituted alkynylsulfanyl, substituted or unsubstituted alkylamino,substituted or unsubstituted alkenylamino, substituted or unsubstitutedalkynylamino, substituted or unsubstituted alkylcarbonyl, substituted orunsubstituted alkenylcarbonyl, substituted or unsubstitutedalkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted alkenylsulfonyl, substituted or unsubstitutedalkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy,substituted or unsubstituted alkenylcarbonyloxy, substituted orunsubstituted alkynylcarbonyloxy, substituted or unsubstitutedalkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted alkylsulfonyloxy, substituted or unsubstitutedalkenylsulfonyloxy, substituted or unsubstituted alkynylsulfonyloxy,substituted or unsubstituted alkyloxysulfonyl, substituted orunsubstituted alkenyloxysulfonyl, substituted or unsubstitutedalkynyloxysulfonyl, substituted or unsubstituted alkylcarbamoyl,substituted or unsubstituted alkenylcarbamoyl, substituted orunsubstituted alkynylcarbamoyl, substituted or unsubstitutedalkylsulfamoyl, substituted or unsubstituted alkenylsulfamoyl,substituted or unsubstituted alkynylsulfamoyl, substituted orunsubstituted alkylcarbonylamino, substituted or unsubstitutedalkenylcarbonylamino, substituted or unsubstituted alkynylcarbonylamino,substituted or unsubstituted alkylsulfonylamino, substituted orunsubstituted alkenylsulfonylamino, substituted or unsubstitutedalkynylsulfonylamino, substituted or unsubstitutedalkyloxycarbonylamino, substituted or unsubstitutedalkenyloxycarbonylamino, substituted or unsubstitutedalkynyloxycarbonylamino, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylamino, substituted or unsubstitutednon-aromatic carbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

R^(5b) is a hydrogen atom, carboxy, carbamoyl, sulfamoyl, sulfo, cyano,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkyloxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted alkylcarbamoyl,substituted or unsubstituted alkenylcarbamoyl, substituted orunsubstituted alkynylcarbamoyl, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, substituted orunsubstituted non-aromatic heterocyclyl, substituted or unsubstitutedaromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, or substituted or unsubstituted non-aromaticheterocyclylcarbamoyl;

Ring Q is a substituted or unsubstituted 5-membered non-aromaticheterocycle or a substituted or unsubstituted 6-membered non-aromaticheterocycle;

Y¹ is N(R⁶), O, or S;

R⁶ is a hydrogen atom, hydroxy, cyano, carboxy, carbamoyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, substituted orunsubstituted alkynyloxy, substituted or unsubstituted aromaticcarbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl,substituted or unsubstituted aromatic heterocyclyl, or substituted orunsubstituted non-aromatic heterocyclyl;

R^(2a) is a group represented by the formula:—(C(R^(2a′))(R^(2b′)))_(n)—R¹;

R^(2b) is a hydrogen atom, halogen, hydroxy, substituted orunsubstituted alkyl, or substituted or unsubstituted alkyloxy;

R^(2a′) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2b′) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2a′) and R^(2b′) which are attached to the same carbon atom may betaken together to form oxo;

R¹ is substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, or substituted or unsubstituted non-aromaticheterocyclyl;

X is N(R^(7a)), C(R^(8a))(R^(8b)), O or S;

R^(7a) is a hydrogen atom, substituted or unsubstituted alkyl, orsubstituted or unsubstituted alkylcarbonyl;

R^(8a) and R^(8b) are each independently a hydrogen atom, halogen,hydroxy, substituted or unsubstituted alkyl, or substituted orunsubstituted alkyloxy;

R^(2c) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2d) is each independently a hydrogen atom, halogen, hydroxy,substituted or unsubstituted alkyl, or substituted or unsubstitutedalkyloxy;

R^(2c) and R^(2d) which are attached to the same carbon atom may betaken together to form a substituted or unsubstituted non-aromaticcarbocycle, or two R^(2c) may be taken together to form a substituted orunsubstituted non-aromatic carbocycle;

R³ is substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, or substituted or unsubstituted non-aromaticcarbocyclyl;

n is an integer from 0 to 4; and

m is an integer from 0 to 4,

provided that the following compounds are excluded:

or a pharmaceutically acceptable salt thereof.

-   (2)

The compound according to any one of the above (1″), (1′), and (1),wherein

the dashed line represents the presence of a bond, or a pharmaceuticallyacceptable salt thereof.

-   (3)

The compound according to any one of the above (1″), (1′), and (1),wherein

or a pharmaceutically acceptable salt thereof.

-   (4)

The compound according to the above (2) or (3), wherein

Ring Q is a substituted or unsubstituted 5-membered saturatedheterocycle or a substituted or unsubstituted 6-membered saturatedheterocycle, or a pharmaceutically acceptable salt thereof.

-   (5)

The compound according to any one of the above (1″), (1′), and (1),wherein

the dashed line represents the absence of a bond, or a pharmaceuticallyacceptable salt thereof.

-   (6)

The compound according to any one of the above (1″), (1′), and (1),wherein

or a pharmaceutically acceptable salt thereof.

-   (7)

The compound according to the above (5) or (6), wherein

Ring Q is a substituted or unsubstituted 5-membered non-aromaticheterocycle, or a pharmaceutically acceptable salt thereof.

-   (8)

The compound according to any one of the above (1″), (1′), and (1) to(7), wherein

-   Z¹ is N,    or a pharmaceutically acceptable salt thereof.-   (9)

The compound according to any one of the above (1″), (1′), and (1) to(8), wherein

Y¹ is O,

or a pharmaceutically acceptable salt thereof.

-   (10)

The compound according to any one of the above (1″), (1′), and (1) to(9), wherein

X is N(R^(7a)),

or a pharmaceutically acceptable salt thereof.

-   (11)

The compound according to any one of the above (1″), (1), and (1) to(10), wherein

R^(7a) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (12)

The compound according to any one of the above (1″), (1), and (1) to(11), wherein

R¹ is substituted or unsubstituted 6-membered aromatic carbocyclyl, orsubstituted or unsubstituted 5- to 6-membered aromatic heterocyclyl, ora pharmaceutically acceptable salt thereof.

-   (13)

The compound according to any one of the above (1″), (1), and (1) to(11), wherein

R¹ is substituted or unsubstituted 6-membered aromatic carbocyclyl, or apharmaceutically acceptable salt thereof.

-   (14)

The compound according to any one of the above (1″), (1), and (1) to(11), wherein

R¹ is 6-membered aromatic carbocyclyl substituted with one or morehalogen atom(s) and optionally substituted with one or more and same ordifferent substituent(s), or 5- to 6-membered aromatic heterocyclylsubstituted with one or more halogen atom(s) and optionally substitutedwith one or more and same or different substituent(s),

or a pharmaceutically acceptable salt thereof.

-   (15)

The compound according to any one of the above (1″), (1), and (1) to(11), wherein

R¹ is 6-membered aromatic carbocyclyl substituted with one or morehalogen atom(s) and optionally substituted with one or more and same ordifferent substituent(s),

or a pharmaceutically acceptable salt thereof.

-   (16)

The compound according to any one of the above (1″), (1), and (1) to(15), wherein

R^(2a′) and R^(2b′) are each a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (17)

The compound according to any one of the above (1″), (1), and (1) to(16), wherein

R^(2b) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (18)

The compound according to any one of the above (1″), (1), and (1) to(17), wherein

R^(5a) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted aromatic carbocyclyl, or substituted or unsubstitutedaromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (19)

The compound according to any one of the above (1″), (1′), and (1) to(17), wherein

R^(5a) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted aromatic carbocyclyl, or substituted orunsubstituted aromatic heterocyclyl, or a pharmaceutically acceptablesalt thereof.

-   (20)

The compound according to any one of the above (1″), (1′), and (1) to(19), wherein

R^(5a′) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted aromatic carbocyclyl, or substituted or unsubstitutedaromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (21)

The compound according to any one of the above (1″), (1′), and (1) to(19), wherein

R^(5a′) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (22)

The compound according to any one of the above (1″), (1′), and (1) to(21), wherein

R^(5b) is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, or substituted or unsubstitutedalkynyl,

or a pharmaceutically acceptable salt thereof.

-   (23)

The compound according to any one of the above (1″), (1′), and (1) to(22), wherein

R^(5b) is a hydrogen atom, or substituted or unsubstituted alkyl,

or a pharmaceutically acceptable salt thereof.

-   (24)

The compound according to any one of the above (1″), (1′), and (1) to(23), wherein

R³ is substituted or unsubstituted 6-membered aromatic carbocyclyl, orsubstituted or unsubstituted 6- to 10-membered aromatic heterocyclyl, ora pharmaceutically acceptable salt thereof.

-   (25)

The compound of any one of the above (1″), (1′), and (1) to (23),wherein

R³ is a group represented by the Formula:

wherein

Ring B is a 6-membered aromatic carbocycle or a 6-membered aromaticheterocycle;

Ring C is a 5-membered aromatic heterocycle;

R^(9a) and R^(9b) are halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkyloxy, substituted or unsubstitutedalkenyloxy, substituted or unsubstituted alkynyloxy, substituted orunsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy,substituted or unsubstituted alkynylsulfonyloxy, substituted orunsubstituted alkyloxysulfonyl, substituted or unsubstitutedalkenyloxysulfonyl, substituted or unsubstituted alkynyloxysulfonyl,substituted or unsubstituted alkylcarbamoyl, substituted orunsubstituted alkenylcarbamoyl, substituted or unsubstitutedalkynylcarbamoyl, substituted or unsubstituted alkylsulfamoyl,substituted or unsubstituted alkenylsulfamoyl, substituted orunsubstituted alkynylsulfamoyl, substituted or unsubstitutedalkylcarbonylamino, substituted or unsubstituted alkenylcarbonylamino,substituted or unsubstituted alkynylcarbonylamino, substituted orunsubstituted alkylsulfonylamino, substituted or unsubstitutedalkenylsulfonylamino, substituted or unsubstituted aromatic carbocyclyl,substituted or unsubstituted non-aromatic carbocyclyl, substituted orunsubstituted aromatic heterocyclyl, substituted or unsubstitutednon-aromatic heterocyclyl, substituted or unsubstituted aromaticcarbocyclyloxy, substituted or unsubstituted non-aromaticcarbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy,substituted or unsubstituted non-aromatic heterocyclyloxy, substitutedor unsubstituted aromatic carbocyclylamino, substituted or unsubstitutednon-aromatic carbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

R^(10a) and R^(10b) are each independently halogen, hydroxy, carboxy,amino, carbamoyl, sulfamoyl, sulfo, cyano, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted orunsubstituted alkenylsulfanyl, substituted or unsubstitutedalkynylsulfanyl, substituted or unsubstituted alkylamino, substituted orunsubstituted alkenylamino, substituted or unsubstituted alkynylamino,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy,substituted or unsubstituted alkynylsulfonyloxy, substituted orunsubstituted alkyloxysulfonyl, substituted or unsubstitutedalkenyloxysulfonyl, substituted or unsubstituted alkynyloxysulfonyl,substituted or unsubstituted alkylcarbamoyl, substituted orunsubstituted alkenylcarbamoyl, substituted or unsubstitutedalkynylcarbamoyl, substituted or unsubstituted alkylsulfamoyl,substituted or unsubstituted alkenylsulfamoyl, substituted orunsubstituted alkynylsulfamoyl, substituted or unsubstitutedalkylcarbonylamino, substituted or unsubstituted alkenylcarbonylamino,substituted or unsubstituted alkynylcarbonylamino, substituted orunsubstituted alkylsulfonylamino, substituted or unsubstitutedalkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

R^(9a), R^(9b), R^(10a) and R^(10b) may be any of the following a) toc):

-   a) R^(9a) and R^(10a), or R^(9b) and R^(10b) are taken together to    form a (C1-C3) bridge, wherein one of the carbon atoms constituting    the bridge may be replaced with an oxygen atom or a nitrogen atom;-   b) R^(9a) and R^(10a) which are attached to the adjacent    ring-constituting atoms, or R^(9b) and R^(10b) which are attached to    the adjacent ring-constituting atoms are taken together to form a    substituted or unsubstituted aromatic carbocycle, a substituted or    unsubstituted non-aromatic carbocycle, a substituted or    unsubstituted aromatic heterocycle, or a substituted or    unsubstituted non-aromatic heterocycle; and-   c) two R^(10a) which are attached to the adjacent ring-constituting    atoms, or two R^(10b) which are attached to the adjacent    ring-constituting atoms are taken together to form a substituted or    unsubstituted aromatic carbocycle, a substituted or unsubstituted    non-aromatic carbocycle, a substituted or unsubstituted aromatic    heterocycle, or a substituted or unsubstituted non-aromatic    heterocycle; and

p1 is an integer from 0 to 3;

p2 is an integer from 0 to 2,

or a pharmaceutically acceptable salt thereof.

-   (26)

The compound according to the above (25), wherein

R³ is a group represented by;

or a pharmaceutically acceptable salt thereof.

-   (27)

The compound according to the above (25) or (26), wherein

R^(9a) and R^(9b) are each halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, or substituted or unsubstitutedalkynyl, or a pharmaceutically acceptable salt thereof.

-   (28)

The compound according to the above (25) or (26), wherein

R^(9a) and R^(9b) are each substituted or unsubstituted alkyl, or apharmaceutically acceptable salt thereof.

-   (29)

The compound according to any one of the above (25) to (28), wherein

R^(10a) and R^(10b) are each independently halogen, hydroxy, amino,carbamoyl, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkenylamino, substituted orunsubstituted alkynylamino, substituted or unsubstituted alkylcarbonyl,substituted or unsubstituted alkenylcarbonyl, substituted orunsubstituted alkynylcarbonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedalkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, or substituted or unsubstituted non-aromaticheterocyclyloxy,

or a pharmaceutically acceptable salt thereof.

-   (30)

The compound according to any one of the above (25) to (28), wherein

R^(10a) and R^(10b) are each independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, or substituted or unsubstitutedalkynyloxy,

or a pharmaceutically acceptable salt thereof.

-   (31)

The compound according to any one of the above (25) to (30), wherein

R^(9a) and R^(10a) which are attached to the adjacent ring-constitutingatoms or R^(9b) and R^(10b) which are attached to the adjacentring-constituting atoms are taken together to form a substituted orunsubstituted aromatic carbocycle, a substituted or unsubstitutednon-aromatic carbocycle, a substituted or unsubstituted aromaticheterocycle, or a substituted or unsubstituted non-aromatic heterocycle,or two R^(10a) which are attached to the adjacent ring-constitutingatoms or two R^(10b) which are attached to the adjacentring-constituting atoms are taken together to form a substituted orunsubstituted aromatic carbocycle, a substituted or unsubstitutednon-aromatic carbocycle, a substituted or unsubstituted aromaticheterocycle, or a substituted or unsubstituted non-aromatic heterocycle,

or a pharmaceutically acceptable salt thereof.

-   (32)

The compound according to any one of the above (25) to (30), wherein

R^(9a) and R^(10a) which are attached to the adjacent ring-constitutingatoms or R^(9b) and R^(10b) which are attached to the adjacentring-constituting atoms are taken together to form a substituted orunsubstituted aromatic heterocycle, or

two R^(10a) which are attached to the adjacent ring-constituting atomsor two R^(10b) which are attached to the adjacent ring-constitutingatoms are taken together to form a substituted or unsubstituted aromaticheterocycle, or a substituted or unsubstituted non-aromatic heterocycle,

or a pharmaceutically acceptable salt thereof.

-   (33)

The compound according to any one of the above (1″), (1′), and (1) to(32), wherein

n is 0,

or a pharmaceutically acceptable salt thereof.

-   (34)

The compound according to any one of the above (1″), (1′), and (1) to(33), wherein

m is 0,

or a pharmaceutically acceptable salt thereof.

-   (35)

The compound according to any one of the above (1″), (1′), and (1) to(34), wherein

R^(2c) and R^(2d) are each independently a hydrogen atom or halogen, ora pharmaceutically acceptable salt thereof.

-   (36)

The compound according to any one of the above (1″), (1′), and (1) to(34), wherein

R^(2c) and R^(2d) are each a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (37)

The compound according to any one of the above (1″), (1′), and (1) to(36), wherein

R⁴ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl,

or a pharmaceutically acceptable salt thereof.

-   (38)

The compound according to any one of the above (1″), (1′), and (1) to(36), wherein

R⁴ is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (39)

The compound according to the above (1″), (1′), and (1), wherein thecompound is selected from the group consisting of Examples I-0059,I-0102, I-0135, I-0142, I-0145, I-0147, I-0149, I-0154, I-0158, I-0161,I-0162, 1-0164, I-0168, I-0171, I-0176, I-0188, I-0192, and I-0201,

or a pharmaceutically acceptable salt thereof.

-   (40)

A P2X₇ receptor inhibitor comprising:

the compound according to any one of the above (1″), (1′), and (1) to(39), or a pharmaceutically acceptable salt thereof.

-   (41)

A pharmaceutical composition comprising:

the compound according to any one of the above (1″), (1′), and (1) to(39), or a pharmaceutically acceptable salt thereof.

-   (42)

The pharmaceutical composition according to the above (41), having anantagonistic activity for the P2X₇ receptor.

-   (43)

The compound according to any one of the above (1″), (1′), and (1) to(39), or a pharmaceutically acceptable salt thereof for use in treatingand/or preventing a disease associated with the P2X₇ receptor.

-   (44)

A method for treating and/or preventing a disease associated with theP2X₇ receptor characterized by administering the compound according toany one of the above (1″), (1′), and (1) to (39), or a pharmaceuticallyacceptable salt thereof.

-   (1001) A pharmaceutical composition comprising the compound    according to any one of the above (1) to (39), or a pharmaceutically    acceptable salt thereof, for oral administration.-   (1002) The pharmaceutical composition according to the above (1001),    which is a tablet, powder, granule, capsule, pill, film, suspension,    emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract,    decoction or tincture.-   (1003) The pharmaceutical composition according to the above (1002),    which is a sugar-coated tablet, film-coated tablet, enteric-coated    tablet, sustained-release tablet, troche tablet, sublingual tablet,    buccal tablet, chewable tablet, orally dispersing tablet, dry syrup,    soft capsule, micro capsule or sustained-release capsule.-   (1004) A pharmaceutical composition comprising the compound    according to any one of the above (1) to (39), or a pharmaceutically    acceptable salt thereof, for parenteral administration.-   (1005) The pharmaceutical composition according to the above (1004),    for dermal, subcutaneous, intravenous, intraarterial, intramuscular,    intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic,    inner ear or vaginal administration.-   (1006) The pharmaceutical composition according to the above (1004)    or (1005), which is injection, infusion, eye drop, nose drop, ear    drop, aerosol, inhalation, lotion, impregnation, liniment,    mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm,    external powder or suppository.-   (1007) A pharmaceutical composition comprising the compound    according to any one of the above (1) to (39), or a pharmaceutically    acceptable salt thereof, for a pediatric or geriatric patient.

Effect of the Invention

The compounds of the present invention have an antagonistic activity forthe P2X₇ receptor, and are useful as a therapeutic and/or preventiveagent for diseases or conditions associated with the P2X₇ receptor.

MODE FOR CARRYING OUT THE INVENTION

Terms used in this description are explained below. Each term, unlessotherwise indicated, has the same meaning when it is used alone ortogether with other terms.

The term “consist of” means having only a component.

The term “comprise” means that an element that is not described is notexcluded without limitations to a component.

“Halogen” includes a fluorine atom, a chlorine atom, a bromine atom andan iodine atom. A fluorine atom and a chlorine atom are preferable.

“Alkyl” includes a C1 to C15, preferably C1 to C10, more preferably C1to C6 and further preferably C1 to C4 linear or branched hydrocarbongroup. For example, it includes methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl,n-nonyl, n-decyl and the like.

A preferred embodiment of “alkyl” is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A more preferredembodiment is methyl, ethyl, n-propyl, isopropyl or tert-butyl.

“Alkenyl” includes a C2 to C15, preferably C2 to C10, more preferably C2to C6 and further preferably C2 to C4 linear or branched hydrocarbongroup having one or more double bond(s) at any position(s). For example,it includes vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl,prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl,isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.

A preferred embodiment of “alkenyl” is vinyl, allyl, propenyl,isopropenyl or butenyl.

“Alkynyl” includes a C2 to C10, preferably C2 to C8, more preferably C2to C6 and further preferably C2 to C4 linear or branched hydrocarbongroup having one or more triple bond(s) at any position(s). For example,it includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl and the like. Furthermore, it may have doublebond(s) at any position(s).

A preferred embodiment of “alkynyl” is ethynyl, propynyl, butynyl orpentynyl.

“Aromatic carbocycle” means a cyclic aromatic hydrocarbon ring which ismonocyclic or polycyclic having two or more rings. For example, itincludes benzene, naphthalene, anthracene, phenanthrene and the like.

A preferred embodiment of “aromatic carbocycle” is benzene.

“Aromatic carbocyclyl” means a cyclic aromatic hydrocarbon group whichis monocyclic or polycyclic having two or more rings. For example, itincludes phenyl, naphthyl, anthryl, phenanthryl and the like.

A preferred embodiment of “aromatic carbocyclyl” is phenyl.

“Non-aromatic carbocycle” means a cyclic saturated hydrocarbon ring or acyclic unsaturated non-aromatic hydrocarbon ring, which is monocyclic orpolycyclic having two or more rings. “Non-aromatic carbocycle”, which ispolycyclic having two or more rings, includes a fused ring wherein anon-aromatic carbocycle, which is monocyclic or polycyclic having two ormore rings, is fused with a ring of the above “aromatic carbocycle”.

In addition, the “non-aromatic carbocycle” also includes a ring having abridge or a ring to form a Spiro ring as follows.

A non-aromatic carbocycle which is monocyclic is preferably C3 to C16,more preferably C3 to C12 and further preferably C4 to C8 carbocycle.For example, it includes cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane,cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene,cyclohexadiene and the like.

A non-aromatic carbocycle which is polycyclic having two or more ringsincludes, for example, indane, indene, acenaphthalene,tetrahydronaphthalene, fluorene and the like.

“Non-aromatic carbocyclyl” means a cyclic saturated hydrocarbon group ora cyclic unsaturated non-aromatic hydrocarbon group, which is monocyclicor polycyclic having two or more rings. “Non-aromatic carbocyclyl”,which is polycyclic having two or more rings, includes a fused ringgroup wherein a non-aromatic carbocyclyl, which is monocyclic orpolycyclic having two or more rings, is fused with a ring of the above“aromatic carbocyclyl”.

In addition, the “non-aromatic carbocyclyl” also includes a group havinga bridge or a group to form a spiro ring as follows:

A non-aromatic carbocyclyl which is monocyclic is preferably C3 to C16,more preferably C3 to C12 and further preferably C4 to C8 carbocyclyl.For example, it includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclohexadienyl and the like.

A non-aromatic carbocyclyl which is polycyclic having two or more ringsincludes, for example, indanyl, indenyl, acenaphthyl,tetrahydronaphthyl, fluorenyl and the like.

“Aromatic heterocycle” means an aromatic ring, which is monocyclic orpolycyclic having two or more rings, containing one or more and same ordifferent of heteroatom(s) selected independently from O, S and N.

“Aromatic heterocycle”, which is polycyclic having two or more rings,includes a fused ring wherein an aromatic heterocycle, which ismonocyclic or polycyclic having two or more rings, is fused with a ringof the above “aromatic carbocycle”.

An aromatic heterocycle which is monocyclic is preferably a 5- to8-membered and more preferably 5- to 6-membered ring. For example, itincludes pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine,pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole,oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.

An aromatic heterocycle which is bicyclic includes, for example, indole,isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline,phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine,benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole,benzisothiazole, benzothiazole, benzothiadiazole, benzofuran,isobenzofuran, benzothiophene, benzotriazole, imidazopyridine,triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine,thiazolopyridine and the like.

An aromatic heterocycle which is polycyclic having three or more ringsincludes, for example, carbazole, acridine, xanthene, phenothiazine,phenoxathiine, phenoxazine, dibenzofuran and the like.

“Aromatic heterocyclyl” means an aromatic cyclyl, which is monocyclic orpolycyclic having two or more rings, containing one or more and same ordifferent of heteroatom(s) selected independently from O, S and N.

“Aromatic heterocyclyl”, which is polycyclic having two or more rings,includes a fused ring group wherein an aromatic heterocyclyl, which ismonocyclic or polycyclic having two or more rings, is fused with a ringof the above “aromatic carbocyclyl”.

An aromatic heterocyclyl which is monocyclic is preferably a 5- to6-membered ring. For example, it includes pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl,triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl,oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.

An aromatic heterocyclyl which is bicyclic includes, for example,indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl,benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl,triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl,thiazolopyridyl and the like.

An aromatic heterocyclyl which is polycyclic having three or more ringsincludes, for example, carbazolyl, acridinyl, xanthenyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.

“Non-aromatic heterocycle” means a non-aromatic ring, which ismonocyclic or polycyclic having two or more rings, containing one ormore and same or different of heteroatom(s) selected independently fromO, S and N.

“Non-aromatic heterocycle”, which is polycyclic having two or morerings, includes a fused ring wherein a non-aromatic heterocycle, whichis monocyclic or polycyclic having two or more ring(s), is fused with aring of the above “aromatic carbocycle”, “non-aromatic carbocycle”and/or “aromatic heterocycle”. The non-aromatic heterocycle, which ispolycyclic having two or more rings, further includes a fused ringwherein an aromatic heterocycle, which is monocyclic or polycyclichaving two or more rings, is fused with a ring of the above“non-aromatic carbocycle”.

In addition, the “non-aromatic heterocycle” also includes a ring havinga bridge or a ring to form a spiro ring as follows.

A non-aromatic heterocycle which is monocyclic is preferably a 3- to8-membered and more preferably 5- to 6-membered ring. For example, itincludes dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine,thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine,imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine,morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine,tetrahydrofuran, tetrahydropyrane, dihydrothiazole, tetrahydrothiazole,tetrahydroisothiazole, dihydrooxazine, hexahydroazepine,tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine,dioxolane, dioxazine, aziridine, dioxoline, oxepane, thiolane, thiine,thiazine and the like.

A non-aromatic heterocycle which is polycyclic having two or more ringsincludes, for example, indoline, isoindolinel, chromane, isochromane andthe like.

“Non-aromatic heterocyclyl” means a non-aromatic cyclyl, which ismonocyclic or polycyclic having two or more rings, containing one ormore and same or different of heteroatom(s) selected independently from0, S and N.

“Non-aromatic heterocyclyl”, which is polycyclic having two or morerings, includes a fused ring group wherein a non-aromatic heterocycle,which is monocyclic or polycyclic having two or more ring(s), is fusedwith a ring of the above “aromatic carbocyclyl”, “non-aromaticcarbocyclyl” and/or “aromatic heterocyclyl”. The non-aromaticheterocyclyl, which is polycyclic having two or more rings, furtherincludes a fused ring wherein an aromatic heterocyclyl, which ismonocyclic or polycyclic having two or more rings, is fused with a ringof the above “non-aromatic carbocyclyl”.

In addition, the “non-aromatic heterocyclyl” also includes a grouphaving a bridge or a group to form a spiro ring as follows:

A non-aromatic heterocyclyl which is monocyclic is preferably a 3- to8-membered and more preferably 5- to 6-membered ring. For example, itincludes dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl,azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl,piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,dihydropyridinyl, tetrahydropyridinyl, tetrahydrofuryl,tetrahydropyranyl, dihydrothiazolinyl, tetrahydrothiazolinyl,tetrahydroisothiazolinyl, dihydrooxazinyl, hexahydroazepinyl,tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl,dioxolanyl, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl,thiinyl, thiazinyl and the like.

A non-aromatic heterocyclyl which is polycyclic having two or more ringsincludes, for example, indolinyl, isoindolinyl, chromanyl, isochromanyland the like.

“Alkyloxy” means a group wherein the above “alkyl” is bonded to anoxygen atom. For example, it includes methyloxy, ethyloxy, n-propyloxy,isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy,pentyloxy, isopentyloxy, hexyloxy and the like.

A preferred embodiment of “alkyloxy” is methyloxy, ethyloxy,n-propyloxy, isopropyloxy or tert-butyloxy.

“Alkenyloxy” means a group wherein the above “alkenyl” is bonded to anoxygen atom. For example, it includes vinyloxy, allyloxy, 1-propenyloxy,2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxyand the like.

“Alkynyloxy” means a group wherein the above “alkynyl” is bonded to anoxygen atom. For example, it includes ethynyloxy, 1-propynyloxy,2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy,2-octynyloxy and the like.

“Alkylsulfanyl” means a group wherein a hydrogen atom bonded to a sulfuratom of a sulfanyl group is replaced with the above “alkyl”. Forexample, it includes methylsulfanyl, ethylsulfanyl, n-propylsulfanyl,isopropylsulfanyl and the like.

“Alkenylsulfanyl” means a group wherein a hydrogen atom bonded to asulfur atom of a sulfanyl group is replaced with the above “alkenyl”.For example, it includes ethylenylsulfanyl, propenylsulfanyl and thelike.

“Alkynylsulfanyl” means a group wherein a hydrogen atom bonded to asulfur atom of a sulfanyl group is replaced with the above “alkynyl”.For example, it includes ethynylsulfanyl, propynylsulfanyl and the like.

“Alkylamino” means a group wherein a hydrogen atom attached to anitrogen atom of an amino group is replaced with the above “alkyl”. Forexample, it includes methylamino, ethylamino, isopropylamino and thelike. Another hydrogen atom attached to the nitrogen atom of the aminogroup may be replaced with the above “alkyl”.

A preferred embodiment of “alkylamino” is methylamino or ethylamino.

“Alkenylamino” means a group wherein a hydrogen atom attached to anitrogen atom of an amino group is replaced with the above “alkenyl”.For example, it includes ethylenylamino, propenylamino and the like.Another hydrogen atom attached to the nitrogen atom of the amino groupmay be replaced with the above “alkyl”.

“Alkynylamino” means a group wherein a hydrogen atom attached to anitrogen atom of an amino group is replaced with the above “alkynyl”.For example, it includes ethynylamino, propynylamino and the like.Another hydrogen atom attached to the nitrogen atom of the amino groupmay be replaced with the above “alkyl”.

“Alkylcarbonyl” means a group wherein the above “alkyl” is bonded to acarbonyl group. For example, it includes methylcarbonyl, ethylcarbonyl,propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl,sec-butylcarbonyl, penthylcarbonyl, isopenthylcarbonyl, hexylcarbonyland the like.

A preferred embodiment of “alkylcarbonyl” is methylcarbonyl,ethylcarbonyl or n-propylcarbonyl.

“Alkenylcarbonyl” means a group wherein the above “alkenyl” is bonded toa carbonyl group. For example, it includes ethylenylcarbonyl,propenylcarbonyl and the like.

“Alkynylcarbonyl” means a group wherein the above “alkynyl” is bonded toa carbonyl group. For example, it includes ethynylcarbonyl,propynylcarbonyl and the like.

“Alkylsulfonyl” means a group wherein the above “alkyl” is bonded to asulfonyl group. For example, it includes methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl,sec-butylsulfonyl and the like.

A preferred embodiment of “alkylsulfonyl” is methylsulfonyl orethylsulfonyl.

“Alkenylsulfonyl” means a group wherein the above “alkenyl” is bonded toa sulfonyl group. For example, it includes ethylenylsulfonyl,propenylsulfonyl and the like.

“Alkynylsulfonyl” means a group wherein the above “alkynyl” is bonded toa sulfonyl group. For example, it includes ethynylsulfonyl,propynylsulfonyl and the like.

“Alkylcarbonyloxy” means a group wherein the above “alkylcarbonyl” isbonded to an oxygen atom. For example, it includes methylcarbonyloxy,ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy,tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and thelike.

A preferred embodiment of “alkylcarbonyloxy” is methylcarbonyloxy orethylcarbonyloxy.

“Alkenylcarbonyloxy” means a group wherein the above “alkenylcarbonyl”is bonded to an oxygen atom. For example, it includesethylenylcarbonyloxy, propenylcarbonyloxy and the like.

“Alkynylcarbonyloxy” means a group wherein the above “alkynylcarbonyl”is bonded to an oxygen atom. For example, it includesethynylcarbonyloxy, propynylcarbonyloxy and the like.

“Alkyloxycarbonyl” means a group wherein the above “alkyloxy” is bondedto a carbonyl group. For example, it includes methyloxycarbonyl,ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl,penthyloxycarbonyl, isopenthyloxycarbonyl, hexyloxycarbonyl and thelike.

A preferred embodiment of “alkyloxycarbonyl” is methyloxycarbonyl,ethyloxycarbonyl or propyloxycarbonyl.

“Alkenyloxycarbonyl” means a group wherein the above “alkenyloxy” isbonded to a carbonyl group. For example, it includesethylenyloxycarbonyl, propenyloxycarbonyl and the like.

“Alkynyloxycarbonyl” means a group wherein the above “alkynyloxy” isbonded to a carbonyl group. For example, it includes ethynyloxycarbonyl,propynyloxycarbonyl and the like.

“Alkylsulfonyloxy” means a group wherein the above “alkylsulfonyl” isbonded to an oxygen atom. For example, it includes methylsulfonyloxy,ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy,tert-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy and thelike.

A preferred embodiment of “alkylsulfonyloxy” is methylsulfonyloxy orethylsulfonyloxy.

“Alkenylsulfonyloxy” means a group wherein the above “alkenylsulfonyl”is bonded to an oxygen atom. For example, it includesethylenylsulfonyloxy, propenylsulfonyloxy and the like.

“Alkynylsulfonyloxy” means a group wherein the above “alkynylsulfonyl”is bonded to an oxygen atom. For example, it includesethynylsulfonyloxy, propynylsulfonyloxy and the like.

“Alkyloxysulfonyl” means a group wherein the above “alkyloxy” is bondedto a sulfonyl group. For example, it includes methyloxysulfonyl,ethyloxysulfonyl, propyloxysulfonyl, isopropyloxysulfonyl,tert-butyloxysulfonyl, isobutyloxysulfonyl, sec-butyloxysulfonyl,pentyloxysulfonyl, isopentyloxysulfonyl, hexyloxysulfonyl and the like.

A preferred embodiment of “alkyloxysulfonyl” is methyloxysulfonyl,ethyloxysulfonyl, or propyloxysulfonyl.

“Alkenyloxysulfonyl” means a group wherein the above “alkenyloxy” isbonded to a sulfonyl group. For example, it includesethylenyloxysulfonyl, propenyloxysulfonyl and the like.

“Alkynyloxysulfonyl” means a group wherein the above “alkynyloxy” isbonded to a sulfonyl group. For example, it includes ethynyloxysulfonyl,propynyloxysulfonyl and the like.

“Alkylcarbamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a carbamoyl group is replaced with the above “alkyl”.For example, it includes methylcarbamoyl, ethylcarbamoyl and the like.Another hydrogen atom bonded to the nitrogen atom of the carbamoyl groupmay be replaced with the above “alkyl”.

“Alkenylcarbamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a carbamoyl group is replaced with the above “alkenyl”.For example, it includes ethylenylcarbamoyl, propenylcarbamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the carbamoylgroup may be replaced with the above “alkyl”.

“Alkynylcarbamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a carbamoyl group is replaced with the above “alkynyl”.For example, it includes ethynylcarbamoyl, propynylcarbamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the carbamoylgroup may be replaced with the above “alkyl”.

“Alkylsulfamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a sulfamoyl group is replaced with the above “alkyl”.For example, it includes methylsulfamoyl, dimethylsulfamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the sulfamoylgroup may be replaced with the above “alkyl”.

“Alkenylsulfamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a sulfamoyl group is replaced with the above “alkenyl”.For example, it includes ethylenylsulfamoyl, propenylsulfamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the carbamoylgroup may be replaced with the above “alkyl”.

“Alkynylsulfamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a sulfamoyl group is replaced with the above “alkynyl”.For example, it includes ethynylsulfamoyl, propynylsulfamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the carbamoylgroup may be replaced with the above “alkyl”.

“Alkylcarbonylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above“alkylcarbonyl”. For example, it includes methylcarbonylamino,ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino,tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylaminoand the like. Another hydrogen atom bonded to the nitrogen atom of theamino group may be replaced with the above “alkyl”.

A preferred embodiment of “alkylcarbonylamino” is methylcarbonylamino orethylcarbonylamino.

“Alkenylcarbonylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above“alkenylcarbonyl”. For example, it includes ethylenylcarbonylamino,propenylcarbonylamino and the like. Another hydrogen atom bonded to thenitrogen atom of the amino group may be replaced with the above “alkyl”.

“Alkynylcarbonylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above“alkynylcarbonyl”. For example, it includes ethynylcarbonylamino,propynylcarbonylamino and the like. Another hydrogen atom bonded to thenitrogen atom of the amino group may be replaced with the above “alkyl”.

“Alkylsulfonylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above“alkylsulfonyl”. For example, it includes methylsulfonylamino,ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino,tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylaminoand the like. Another hydrogen atom bonded to the nitrogen atom of theamino group may be replaced with the above “alkyl”.

A preferred embodiment of “alkylsulfonylamino” is methylsulfonylamino orethylsulfonylamino.

“Alkenylsulfonylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above“alkenylsulfonyl”. For example, it includes ethylenylsulfonylamino,propenylsulfonylamino and the like. Another hydrogen atom bonded to thenitrogen atom of the amino group may be replaced with the above “alkyl”.

“Alkynylsulfonylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above“alkynylsulfonyl”. For example, it includes ethynylsulfonylamino,propynylsulfonylamino and the like. Another hydrogen atom bonded to thenitrogen atom of the amino group may be replaced with the above “alkyl”.

“Alkyloxycarbonylamino” means a group wherein a hydrogen atom bonded toa nitrogen atom of an amino group is replaced with the above“alkyloxycarbonyl”. For example, it includes methyloxycarbonylamino,ethyloxycarbonylamino, propyloxycarbonylamino,isopropyloxycarbonylamino, tert-butyloxycarbonylamino,isobutyloxycarbonylamino, sec-butyloxycarbonylamino,pentyloxycarbonylamino, isopentyloxycarbonylamino, hexyloxycarbonylaminoand the like. Another hydrogen atom bonded to the nitrogen atom of theamino group may be replaced with the above “alkyl”.

A preferred embodiment of “alkyloxycarbonyl” is methyloxycarbonylamino,ethyloxycarbonylamino, propyloxycarbonylamino and the like.

“Alkenyloxycarbonylamino” means a group wherein a hydrogen atom bondedto a nitrogen atom of an amino group is replaced with the above“alkenyloxycarbonyl”. For example, it includesethylenyloxycarbonylamino, propenyloxycarbonylamino and the like.Another hydrogen atom bonded to the nitrogen atom of the amino group maybe replaced with the above “alkyl”.

“Alkynyloxycarbonylamino” means a group wherein a hydrogen atom bondedto a nitrogen atom of an amino group is replaced with the above“alkynyloxycarbonyl”. For example, it includes ethynyloxycarbonylamino,propynyloxycarbonylamino and the like. Another hydrogen atom bonded tothe nitrogen atom of the amino group may be replaced with the above“alkyl”.

“Alkylimino” means a group wherein a hydrogen atom bonded to a nitrogenatom of an imino group is replaced with the above “alkyl”. For example,it includes methylimino, ethylimino, n-propylimino, isopropylimino andthe like.

“Alkyloxyimino” means a group wherein a hydrogen atom bonded to anitrogen atom of an imino group is replaced with the above “alkyloxy”.For example, it includes methyloxyimino, ethyloxyimino,n-propyloxyimino, isopropyloxyimino and the like.

The “aromatic carbocycle” part of “aromatic carbocyclyloxy”, “aromaticcarbocyclylamino”, “aromatic carbocyclylsulfanyl”, “aromaticcarbocyclylcarbonyl”, “aromatic carbocyclylsulfonyl”, “aromaticcarbocyclylcarbonyloxy”, “aromatic carbocyclylsulfonyloxy”, “aromaticcarbocyclyloxycarbonyl”, “aromatic carbocyclyloxysulfonyl”, “aromaticcarbocyclylcarbamoyl”, “aromatic carbocyclylsulfamoyl”, “aromaticcarbocyclylcarbonylamino”, “aromatic carbocyclylsulfonylamino”, and“aromatic carbocyclyloxycarbonylamino” is the same as the above“aromatic carbocyclyl”.

“Aromatic carbocyclyloxy” means a group wherein “aromatic carbocycle” isbonded to an oxygen atom. For example, it includes phenyloxy,naphthyloxy and the like.

“Aromatic carbocyclylamino” means a group wherein a hydrogen atomattached to a nitrogen atom of an amino group is replaced with the“aromatic carbocycle”. For example, it includes phenylamino,naphthylamino and the like. Another hydrogen atom bonded to the nitrogenatom of the amino group may be replaced with the above “alkyl”

“Aromatic carbocyclylsulfanyl” means a group wherein a hydrogen atombonded to a sulfur atom of a sulfanyl group is replaced with “aromaticcarbocycle”. For example, it includes phenylsulfanyl, naphthylsulfanyland the like.

“Aromatic carbocyclylcarbonyl” means a group wherein “aromaticcarbocycle” is bonded to a carbonyl group. For example, it includesphenylcarbonyl, naphthylcarbonyl and the like.

“Aromatic carbocyclylsulfonyl” means a group wherein “aromaticcarbocycle” is bonded to a sulfonyl group. For example, it includesphenylsulfonyl, naphthylsulfonyl and the like.

“Aromatic carbocyclylcarbonyloxy” means a group wherein the above“aromatic carbocyclylcarbonyl” is bonded to an oxygen atom. For example,it includes phenylcarbonyloxy, naphthylcarbonyloxy and the like.

“Aromatic carbocyclylsulfonyloxy” means a group wherein the above“aromatic carbocyclylsulfonyl” is bonded to an oxygen atom. For example,it includes phenylsulfonyloxy, naphthylsulfonyloxy and the like.

“Aromatic carbocyclyloxycarbonyl” means a group wherein the above“aromatic carbocyclyloxy” is bonded to a carbonyl group. For example, itincludes phenyloxycarbonyl, naphthyloxycarbonyl and the like.

“Aromatic carbocyclyloxysulfonyl” means a group wherein the above“aromatic carbocyclyloxy” is bonded to a sulfonyl group. For example, itincludes phenyloxysulfonyl, naphthyloxysulfonyl and the like.

“Aromatic carbocyclylcarbamoyl” means a group wherein a hydrogen atombonded to a nitrogen atom of a carbamoyl group is replaced with the“aromatic carbocycle”. For example, it includes phenylcarbamoyl,naphthylcarbamoyl and the like. Another hydrogen atom bonded to thenitrogen atom of the carbamoyl group may be replaced with the above“alkyl”.

“Aromatic carbocyclylsulfamoyl” means a group wherein a hydrogen atombonded to a nitrogen atom of a sulfamoyl group is replaced with the“aromatic carbocycle”. For example, it includes phenylsulfamoyl,naphthylsulfamoyl and the like. Another hydrogen atom bonded to thenitrogen atom of the sulfamoyl group may be replaced with the above“alkyl”.

“Aromatic carbocyclylcarbonylamino” means a group wherein a hydrogenatom attached to a nitrogen atom of an amino group is replaced with theabove “aromatic carbocyclylcarbonyl”. For example, it includesphenylcarbonylamino, naphthylcarbonylamino and the like. Anotherhydrogen atom bonded to the nitrogen atom of the amino group may bereplaced with the above “alkyl”.

“Aromatic carbocyclylsulfonylamino” means a group wherein a hydrogenatom bonded to a nitrogen atom of an amino group is replaced with theabove “aromatic carbocyclylsulfonyl”. For example, it includesphenylsulfonylamino, naphthylsulfonylamino and the like. Anotherhydrogen atom bonded to the nitrogen atom of the amino group may bereplaced with the above “alkyl”.

“Aromatic carbocyclyloxycarbonylamino” means a group wherein a hydrogenatom attached to a nitrogen atom of an amino group is replaced with theabove “aromatic carbocyclyloxycarbonyl”. For example, it includesphenyloxycarbonylamino, naphthyloxycarbonylamino and the like. Anotherhydrogen atom bonded to the nitrogen atom of the amino group may bereplaced with the above “alkyl”.

The “non-aromatic carbocycle” part of “non-aromatic carbocyclyloxy”,“non-aromatic carbocyclylamino”, “non-aromatic carbocyclylsulfanyl”,“non-aromatic carbocyclylcarbonyl”, “non-aromatic carbocyclylsulfonyl”,“non-aromatic carbocyclylcarbonyloxy”, “non-aromaticcarbocyclylsulfonyloxy”, “non-aromatic carbocyclyloxycarbonyl”,“non-aromatic carbocyclyloxysulfonyl”, “non-aromaticcarbocyclylcarbamoyl”, “non-aromatic carbocyclylsulfamoyl”,“non-aromatic carbocyclylcarbonylamino”, “non-aromaticcarbocyclylsulfonylamino”, and “non-aromaticcarbocyclyloxycarbonylamino” is the same as the above “non-aromaticcarbocyclyl”.

“Non-aromatic carbocyclyloxy” means a group wherein “non-aromaticcarbocycle” is bonded to an oxygen atom. For example, it includescyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like.

“Non-aromatic carbocyclylamino” means a group wherein a hydrogen atomattached to a nitrogen atom of an amino group is replaced with the“non-aromatic carbocycle”. For example, it includes cyclopropylamino,cyclohexylamino, cyclohexenylamino and the like. Another hydrogen atombonded to the nitrogen atom of the amino group may be replaced with theabove “alkyl”.

“Non-aromatic carbocyclylsulfanyl” means a group wherein a hydrogen atombonded to a sulfur atom of a sulfanyl group is replaced with“non-aromatic carbocycle”. For example, it includes cyclopropylsulfanyl,cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.

“Non-aromatic carbocyclylcarbonyl” means a group wherein “non-aromaticcarbocycle” is bonded to a carbonyl group. For example, it includescyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and thelike.

“Non-aromatic carbocyclylsulfonyl” means a group wherein “non-aromaticcarbocycle” is bonded to a sulfonyl group. For example, it includescyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and thelike.

“Non-aromatic carbocyclylcarbonyloxy” means a group wherein the above“non-aromatic carbocyclylcarbonyl” is bonded to an oxygen atom. Forexample, it includes cyclopropylcarbonyloxy, cyclohexylcarbonyloxy,cyclohexenylcarbonyloxy and the like.

“Non-aromatic carbocyclylsulfonyloxy” means a group wherein the above“non-aromatic carbocyclylsulfonyl” is bonded to an oxygen atom. Forexample, it includes cyclopropylsulfonyloxy, cyclohexylsulfonyloxy,cyclohexenylsulfonyloxy and the like.

Non-aromatic carbocyclyloxycarbonyl” means a group wherein the above“non-aromatic carbocyclyloxy” is bonded to a carbonyl group. Forexample, it includes cyclopropyloxycarbonyl, cyclohexyloxycarbonyl,cyclohexenyloxycarbonyl and the like.

“Non-aromatic carbocyclyloxysulfonyl” means a group wherein the above“non-aromatic carbocyclyloxy” is bonded to a sulfonyl group. Forexample, it includes cyclopropyloxysulfonyl, cyclohexyloxysulfonyl,cyclohexenyloxysulfonyl and the like.

“Non-aromatic carbocyclylcarbamoyl” means a group wherein a hydrogenatom bonded to a nitrogen atom of a carbamoyl group is replaced with the“non-aromatic carbocycle”. For example, it includescyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the carbamoylgroup may be replaced with the above “alkyl”.

“Non-aromatic carbocyclylsulfamoyl” means a group wherein a hydrogenatom bonded to a nitrogen atom of a sulfamoyl group is replaced with the“non-aromatic carbocycle”. For example, it includescyclopropylsulfamoyl, cyclohexylsulfamoyl, cyclohexenylsulfamoyl and thelike. Another hydrogen atom bonded to the nitrogen atom of the sulfamoylgroup may be replaced with the above “alkyl”.

“Non-aromatic carbocyclylcarbonylamino” means a group wherein a hydrogenatom attached to a nitrogen atom of an amino group is replaced with theabove “non-aromatic carbocyclylcarbonyl”. For example, it includescyclopropylcarbonylamino, cyclohexylcarbonylamino,cyclohexenylcarbonylamino and the like. Another hydrogen atom bonded tothe nitrogen atom of the amino group may be replaced with the above“alkyl”.

“Non-aromatic carbocyclylsulfonylamino” means a group wherein a hydrogenatom bonded to a nitrogen atom of an amino group is replaced with theabove “non-aromatic carbocyclylsulfonyl”. For example, it includescyclopropylsulfonylamino, cyclohexylsulfonylamino,cyclohexenylsulfonylamino and the like. Another hydrogen atom bonded tothe nitrogen atom of the amino group may be replaced with the above“alkyl”

“Non-aromatic carbocyclyloxycarbonylamino” means a group wherein ahydrogen atom attached to a nitrogen atom of an amino group is replacedwith the above “non-aromatic carbocyclyloxycarbonyl”. For example, itincludes cyclopropyloxycarbonylamino, cyclohexyloxycarbonylamino,cyclohexenyloxycarbonylamino and the like. Another hydrogen atom bondedto the nitrogen atom of the amino group may be replaced with the above“alkyl”.

The “aromatic heterocycle” part of “aromatic heterocyclyloxy”, “aromaticheterocyclylamino”, “aromatic heterocyclylsulfanyl”, “aromaticheterocyclylcarbonyl”, “aromatic heterocyclylsulfonyl”, “aromaticheterocyclylcarbonyloxy”, “aromatic heterocyclylsulfonyloxy”, “aromaticheterocyclyloxycarbonyl”, “aromatic heterocyclyloxysulfonyl”, “aromaticheterocyclylcarbamoyl”, “aromatic heterocyclylsulfamoyl”, “aromaticheterocyclylcarbonylamino”, “aromatic heterocyclylsulfonylamino”, and“aromatic heterocyclyloxycarbonylamino” is the same as the above“aromatic heterocyclyl”.

“Aromatic heterocyclyloxy” means a group wherein “aromatic heterocycle”is bonded to an oxygen atom. For example, it includes pyridyloxy,oxazolyloxy and the like.

“Aromatic heterocyclylamino” means a group wherein a hydrogen atomattached to a nitrogen atom of an amino group is replaced with the“aromatic heterocycle”. For example, it includes pyridylamino,oxazolylamino and the like. Another hydrogen atom bonded to the nitrogenatom of the amino group may be replaced with the above “alkyl”.

“Aromatic heterocyclylsulfanyl” means a group wherein a hydrogen atombonded to a sulfur atom of a sulfanyl group is replaced with “aromaticheterocycle”. For example, it includes pyridylsulfanyl, oxazolylsulfanyland the like.

“Aromatic heterocyclylcarbonyl” means a group wherein “aromaticheterocycle” is bonded to a carbonyl group. For example, it includespyridylcarbonyl, oxazolylcarbonyl and the like.

“Aromatic heterocyclylsulfonyl” means a group wherein “aromaticheterocycle” is bonded to a sulfonyl group. For example, it includespyridylsulfonyl, oxazolylsulfonyl and the like.

“Aromatic heterocyclylcarbonyloxy” means a group wherein the above“aromatic heterocyclylcarbonyl” is bonded to an oxygen atom. Forexample, it includes pyridylcarbonyloxy, oxazolylcarbonyloxy and thelike.

“Aromatic heterocyclylsulfonyloxy” means a group wherein the above“aromatic heterocyclylsulfonyl” is bonded to an oxygen atom. Forexample, it includes pyridylsulfonyloxy, oxazolylsulfonyloxy and thelike.

“Aromatic heterocyclyloxycarbonyl” means a group wherein the above“aromatic heterocyclyloxy” is bonded to a carbonyl group. For example,it includes pyridyloxycarbonyl, oxazolyloxycarbonyl and the like.

“Aromatic heterocyclyloxysulfonyl” means a group wherein the above“aromatic heterocyclyloxy” is bonded to a sulfonyl group. For example,it includes pyridyloxysulfonyl, oxazolyloxysulfonyl and the like.

“Aromatic heterocyclylcarbamoyl” means a group wherein a hydrogen atombonded to a nitrogen atom of a carbamoyl group is replaced with the“aromatic heterocycle”. For example, it includes pyridylcarbamoyl,oxazolylcarbamoyl and the like. Another hydrogen atom bonded to thenitrogen atom of the carbamoyl group may be replaced with the above“alkyl”.

“Aromatic heterocyclylsulfamoyl” means a group wherein a hydrogen atombonded to a nitrogen atom of a sulfamoyl group is replaced with the“aromatic heterocycle”. For example, it includes pyridylsulfamoyl,oxazolylsulfamoyl and the like. Another hydrogen atom bonded to thenitrogen atom of the sulfamoyl group may be replaced with the above“alkyl”.

“Aromatic heterocyclylcarbonylamino” means a group wherein a hydrogenatom attached to a nitrogen atom of an amino group is replaced with theabove “aromatic heterocyclylcarbonyl”. For example, it includespyridylcarbonylamino, oxazolylcarbonylamino and the like. Anotherhydrogen atom bonded to the nitrogen atom of the amino group may bereplaced with the above “alkyl”.

“Aromatic heterocyclylsulfonylamino” means a group wherein a hydrogenatom bonded to a nitrogen atom of an amino group is replaced with theabove “aromatic heterocyclylsulfonyl”. For example, it includespyridylsulfonylamino, oxazolylsulfonylamino and the like. Anotherhydrogen atom bonded to the nitrogen atom of the amino group may bereplaced with the above “alkyl”.

“Aromatic heterocyclyloxycarbonylamino” means a group wherein a hydrogenatom attached to a nitrogen atom of an amino group is replaced with theabove “aromatic heterocyclyloxycarbonyl”. For example, it includespyridyloxycarbonylamino, oxazolyloxycarbonylamino and the like. Anotherhydrogen atom bonded to the nitrogen atom of the amino group may bereplaced with the above “alkyl”.

The “non-aromatic heterocycle” part of “non-aromatic heterocyclyloxy”,“non-aromatic heterocyclylamino”, “non-aromatic heterocyclylsulfanyl”,“non-aromatic heterocyclylcarbonyl”, “non-aromaticheterocyclylsulfonyl”, “non-aromatic heterocyclylcarbonyloxy”,“non-aromatic heterocyclylsulfonyloxy”, “non-aromaticheterocyclyloxycarbonyl”, “non-aromatic heterocyclyloxysulfonyl”,“non-aromatic heterocyclylcarbamoyl”, “non-aromaticheterocyclylsulfamoyl”, “non-aromatic heterocyclylcarbonylamino”,“non-aromatic heterocyclylsulfonylamino”, and “non-aromaticheterocyclyloxycarbonylamino” is the same as the above “non-aromaticheterocyclyl”.

“Non-aromatic heterocyclyloxy” means a group wherein “non-aromaticheterocycle” is bonded to an oxygen atom. For example, it includespiperidinyloxy, tetrahydrofuryloxy and the like.

“Non-aromatic heterocyclylamino” means a group wherein a hydrogen atomattached to a nitrogen atom of an amino group is replaced with the“non-aromatic heterocycle”. For example, it includes piperidinylamino,tetrahydrofurylamino and the like. Another hydrogen atom bonded to thenitrogen atom of the amino group may be replaced with the above “alkyl”.

“Non-aromatic heterocyclylsulfanyl” means a group wherein a hydrogenatom bonded to a sulfur atom of a sulfanyl group is replaced with“non-aromatic heterocycle”. For example, it includespiperidinylsulfanyl, tetrahydrofurylsulfanyl and the like.

“Non-aromatic heterocyclylcarbonyl” means a group wherein “non-aromaticheterocycle” is bonded to a carbonyl group. For example, it includespiperidinylcarbonyl, tetrahydrofurylcarbonyl and the like.

“Non-aromatic heterocyclylsulfonyl” means a group wherein “non-aromaticheterocycle” is bonded to a sulfonyl group. For example, it includespiperidinylsulfonyl, tetrahydrofurylsulfonyl and the like.

“Non-aromatic heterocyclylcarbonyloxy” means a group wherein the above“non-aromatic heterocyclylcarbonyl” is bonded to an oxygen atom. Forexample, it includes piperidinylcarbonyloxy, tetrahydrofurylcarbonyloxyand the like.

“Non-aromatic heterocyclylsulfonyloxy” means a group wherein the above“non-aromatic heterocyclylsulfonyl” is bonded to an oxygen atom. Forexample, it includes piperidinylsulfonyloxy, tetrahydrofurylsulfonyloxyand the like.

“Non-aromatic heterocyclyloxycarbonyl” means a group wherein the above“non-aromatic heterocyclyloxy” is bonded to a carbonyl group. Forexample, it includes piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyland the like.

“Non-aromatic heterocyclyloxysulfonyl” means a group wherein the above“non-aromatic heterocyclyloxy” is bonded to a sulfonyl group. Forexample, it includes piperidinyloxysulfonyl, tetrahydrofuryloxysulfonyland the like.

“Non-aromatic heterocyclylcarbamoyl” means a group wherein a hydrogenatom bonded to a nitrogen atom of a carbamoyl group is replaced with the“non-aromatic heterocycle”. For example, it includespiperidinylcarbamoyl, tetrahydrofurylcarbamoyl and the like. Anotherhydrogen atom bonded to the nitrogen atom of the carbamoyl group may bereplaced with the above “alkyl”.

“Non-aromatic heterocyclylsulfamoyl” means a group wherein a hydrogenatom bonded to a nitrogen atom of a sulfamoyl group is replaced with the“non-aromatic heterocycle”. For example, it includespiperidinylsulfamoyl, tetrahydrofurylsulfamoyl and the like. Anotherhydrogen atom bonded to the nitrogen atom of the sulfamoyl group may bereplaced with the above “alkyl”.

“Non-aromatic heterocyclylcarbonylamino” means a group wherein ahydrogen atom attached to a nitrogen atom of an amino group is replacedwith the above “non-aromatic heterocyclylcarbonyl”. For example, itincludes piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and thelike. Another hydrogen atom bonded to the nitrogen atom of the aminogroup may be replaced with the above “alkyl”.

“Non-aromatic heterocyclylsulfonylamino” means a group wherein ahydrogen atom bonded to a nitrogen atom of an amino group is replacedwith the above “non-aromatic heterocyclylsulfonyl”. For example, itincludes piperidinylsulfonylamino, tetrahydrofurylsulfonylamino and thelike. Another hydrogen atom bonded to the nitrogen atom of the aminogroup may be replaced with the above “alkyl”.

“Non-aromatic heterocyclyloxycarbonylamino” means a group wherein ahydrogen atom attached to a nitrogen atom of an amino group is replacedwith the above “non-aromatic heterocyclyloxycarbonyl”. For example, itincludes piperidinyloxycarbonylamino, tetrahydrofuryloxycarbonylaminoand the like. Another hydrogen atom bonded to the nitrogen atom of theamino group may be replaced with the above “alkyl”.

“Haloalkyl” means a group wherein one or more “halogen” described aboveis bonded to the above “alkyl”. For example, it includesmonofluoromethyl, monofluoroethyl, monofluoropropyl,2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.

A preferred embodiment of “haloalkyl” is trifluoromethyl ortrichloromethyl.

“Haloalkyloxy” means a group wherein the above “haloalkyl” is bonded toan oxygen atom. For example, it includes monofluoromethoxy,monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy,trichloroethoxy and the like.

A preferred embodiment of “haloalkyloxy” is trifluoromethoxy ortrichloromethoxy.

“Haloalkylamino” means a group wherein a hydrogen atom bonded to anitrogen atom of an amino group is replaced with the above “haloalkyl”.For example, it includes monofluoromethylamino, monofluoroethylamino,trifluoromethylamino, trichloromethylamino, trifluoroethylamino,trichloroethylamino and the like. Another hydrogen atom bonded to thenitrogen atom of the amino group may be replaced with the above “alkyl”or the above “haloalkyl”.

A preferred embodiment of “haloalkylamino” is trifluoromethylamino ortrichloromethylamino.

“Haloalkylsulfanyl” means a group wherein the above “haloalkyl” isbonded to a sulfanyl group. For example, it includesmonofluoromethylsulfanyl, monofluoroethylsulfanyl,trifluoromethylsulfanyl, trichloromethylsulfanyl,trifluoroethylsulfanyl, trichloroethylsulfanyl and the like.

A preferred embodiment of “haloalkylsulfanyl” is trifluoromethylsulfanylor trichloromethylsulfanyl.

“Haloalkylcarbonyl” means a group wherein the above “haloalkyl” isbonded to a carbonyl group. For example, it includesmonofluoromethylcarbonyl, monofluoroethylcarbonyl,trifluoromethylcarbonyl, trichloromethylcarbonyl,trifluoroethylcarbonyl, trichloroethylcarbonyl and the like.

A preferred embodiment of “haloalkylcarbonyl” is trifluoromethylcarbonylor trichloromethylcarbonyl.

“Haloalkylsulfonyl” means a group wherein the above “haloalkyl” isbonded to a sulfonyl group. For example, it includesmonofluoromethylsulfonyl, monofluoroethylsulfonyl,trifluoromethylsulfonyl, trichloromethylsulfonyl,trifluoroethylsulfonyl, trichloroethylsulfonyl and the like.

A preferred embodiment of “haloalkylsulfonyl” is trifluoromethylsulfonylor trichloromethylsulfonyl.

“Haloalkylcarbamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a carbamoyl group is replaced with the above“haloalkyl”. For example, it includes monofluoromethylcarbamoyl,monofluoroethylcarbamoyl, trifluoromethylcarbamoyl,trichloromethylcarbamoyl, trifluoroethylcarbamoyl,trichloroethylcarbamoyl and the like. Another hydrogen atom bonded tothe nitrogen atom of the carbamoyl group may be replaced with the above“alkyl” or the above “haloalkyl”.

A preferred embodiment of “haloalkylcarbamoyl” istrifluoromethylcarbamoyl or trichloromethylcarbamoyl.

“Haloalkylsulfamoyl” means a group wherein a hydrogen atom bonded to anitrogen atom of a sulfamoyl group is replaced with the above“haloalkyl”. For example, it includes monofluoromethylsulfamoyl,monofluoroethylsulfamoyl, trifluoromethylsulfamoyl,trichloromethylsulfamoyl, trifluoroethylsulfamoyl,trichloroethylsulfamoyl and the like. Another hydrogen atom bonded tothe nitrogen atom of the sulfamoyl group may be replaced with the above“alkyl” or the above “haloalkyl”.

A preferred embodiment of “haloalkylsulfamoyl” istrifluoromethylsulfamoyl or trichloromethylsulfamoyl.

“Haloalkylcarbonylamino” means a group wherein a hydrogen atom bonded toa nitrogen atom of an amino group is replaced with the above“haloalkylcarbonyl”. For example, it includesmonofluoromethylcarbonylamino, monofluoroethylcarbonylamino,trifluoromethylcarbonylamino, trichloromethylcarbonylamino,trifluoroethylcarbonylamino, trichloroethylcarbonylamino and the like.Another hydrogen atom bonded to the nitrogen atom of the amino group maybe replaced with the above “alkyl” or the above “haloalkyl”.

A preferred embodiment of “haloalkylcarbonylamino” istrifluoromethylcarbonylamino or trichloromethylcarbonylamino.

“Haloalkylsulfonylamino” means a group wherein a hydrogen atom bonded toa nitrogen atom of an amino group is replaced with the above“haloalkylsulfonyl”. For example, it includesmonofluoromethylsulfonylamino, monofluoroethylsulfonylamino,trifluoromethylsulfonylamino, trichloromethylsulfonylamino,trifluoroethylsulfonylamino, trichloroethylsulfonylamino and the like.Another hydrogen atom bonded to the nitrogen atom of the amino group maybe replaced with the above “alkyl” or the above “haloalkyl”.

A preferred embodiment of “haloalkylsulfonylamino” istrifluoromethylsulfonylamino or trichloromethylsulfonylamino.

“Haloalkylcarbonyloxy” means a group wherein the above“haloalkylcarbonyl” is bonded to an oxygen atom. For example, itincludes monofluoromethylcarbonyloxy, monofluoroethylcarbonyloxy,trifluoromethylcarbonyloxy, trichloromethylcarbonyloxy,trifluoroethylcarbonyloxy, trichloroethylcarbonyloxy and the like.

A preferred embodiment of “haloalkylcarbonyloxy” istrifluoromethylcarbonyloxy or trichloromethylcarbonyloxy.

“Haloalkylsulfonyloxy” means a group wherein the above“haloalkylsulfonyl” is bonded to an oxygen atom. For example, itincludes monofluoromethylsulfonyloxy, monofluoroethylsulfonyloxy,trifluoromethylsulfonyloxy, trichloromethylsulfonyloxy,trifluoroethylsulfonyloxy, trichloroethylsulfonyloxy and the like.

A preferred embodiment of “haloalkylsulfonyloxy” istrifluoromethylsulfonyloxy or trichloromethylsulfonyloxy.

“Haloalkyloxycarbonyl” means a group wherein the above “haloalkyloxy” isbonded to a carbonyl group. For example, it includesmonofluoromethyloxycarbonyl, monofluoroethyloxycarbonyl,trifluoromethyloxycarbonyl, trichloromethyloxycarbonyl,trifluoroethyloxycarbonyl, trichloroethyloxycarbonyl and the like.

A preferred embodiment of “haloalkyloxycarbonyl” istrifluoromethyloxycarbonyl or trichloromethyloxycarbonyl.

“Haloalkyloxysulfonyl” means a group wherein the above “haloalkyloxy” isbonded to a sulfonyl group. For example, it includesmonofluoromethyloxysulfonyl, monofluoroethyloxysulfonyl,trifluoromethyloxysulfonyl, trichloromethyloxysulfonyl,trifluoroethyloxysulfonyl, trichloroethyloxysulfonyl and the like.

A preferred embodiment of “haloalkyloxysulfonyl” istrifluoromethyloxysulfonyl or trichloromethyloxysulfonyl.

The substituents of “substituted or unsubstituted alkyl” include thesubstituent group A. A carbon atom at any position(s) may be bonded toone or more group(s) selected from the substituent group A.

The substituent group A: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, formyl, imino, hydroxyimino, cyanoimino,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group C2, alkylamino optionally substituted with one ormore group(s) selected from the substituent group C2, alkylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group C2, alkylimino optionally substituted with one or moregroup(s) selected from the substituent group C2, alkyloxyiminooptionally substituted with one or more group(s) selected from thesubstituent group C2, alkylcarbonyl optionally substituted with one ormore group(s) selected from the substituent group C2, alkylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group C2, alkylcarbonylamino optionally substituted with oneor more group(s) selected from the substituent group C2,alkylsulfonylamino optionally substituted with one or more group(s)selected from the substituent group C2, alkylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup C2, alkylsulfamoyl optionally substituted with one or moregroup(s) selected from the substituent group C2, alkylcarbonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group C2, alkyloxycarbonyl optionally substituted with oneor more group(s) selected from the substituent group C2,alkylsulfonyloxy optionally substituted with one or more group(s)selected from the substituent group C2, alkyloxysulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup C2, aromatic carbocyclyl optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromatic carbocyclyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclyl optionally substituted withone or more group(s) selected from the substituent group E, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group E, aromatic carbocyclyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic carbocyclyloxy optionally substituted with one ormore group(s) selected from the substituent group E, aromaticheterocyclyloxy optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylsulfanyl optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylsulfanyl optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfanyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylamino optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylamino optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylaminooptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylcarbonyl optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylcarbonyl optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylcarbonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylsulfonyl optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylsulfonyl optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic carbocyclylcarbonylamino optionally substitutedwith one or more group(s) selected from the substituent group E,aromatic heterocyclylcarbonylamino optionally substituted with one ormore group(s) selected from the substituent group E, non-aromaticheterocyclylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticcarbocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticcarbocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticheterocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticcarbocyclylcarbamoyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic carbocyclylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclylcarbamoyl optionally substituted withone or more group(s) selected from the substituent group E, aromaticcarbocyclylsulfamoyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic carbocyclylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclylsulfamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclylsulfamoyl optionally substituted withone or more group(s) selected from the substituent group E, aromaticcarbocyclyloxycarbonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromaticcarbocyclyloxycarbonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclyloxycarbonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclyloxycarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclyloxysulfonyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclyloxysulfonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclyloxysulfonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclyloxysulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclylcarbonyloxy optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclylcarbonyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclylcarbonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclylcarbonyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclylsulfonyloxy optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclylsulfonyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclylsulfonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, and non-aromatic heterocyclylsulfonyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylamino”, “substituted or unsubstitutedalkenylamino”, “substituted or unsubstituted alkynylamino”, “substitutedor unsubstituted alkylcarbonyl”, “substituted or unsubstitutedalkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”,“substituted or unsubstituted alkylsulfonyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstitutedalkynylsulfonyl”, “substituted or unsubstituted alkylcarbonyloxy”,“substituted or unsubstituted alkenylcarbonyloxy”, “substituted orunsubstituted alkynylcarbonyloxy”, “substituted or unsubstitutedalkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”,“substituted or unsubstituted alkynyloxycarbonyl”, “substituted orunsubstituted alkylsulfonyloxy”, “substituted or unsubstitutedalkenylsulfonyloxy”, “substituted or unsubstituted alkynylsulfonyloxy”,“substituted or unsubstituted alkyloxysulfonyl”, “substituted orunsubstituted alkenyloxysulfonyl”, “substituted or unsubstitutedalkynyloxysulfonyl”, “substituted or unsubstituted alkylcarbamoyl”,“substituted or unsubstituted alkenylcarbamoyl”, “substituted orunsubstituted alkynylcarbamoyl”, “substituted or unsubstitutedalkylsulfamoyl”, “substituted or unsubstituted alkenylsulfamoyl”,“substituted or unsubstituted alkynylsulfamoyl”, “substituted orunsubstituted alkylcarbonylamino”, “substituted or unsubstitutedalkenylcarbonylamino”, “substituted or unsubstitutedalkynylcarbonylamino”, “substituted or unsubstitutedalkylsulfonylamino”, “substituted or unsubstitutedalkenylsulfonylamino”, “substituted or unsubstitutedalkyloxycarbonylamino”, “substituted or unsubstitutedalkenyloxycarbonylamino”, and “substituted or unsubstitutedalkynyloxycarbonylamino” include the substituent group B. A carbon atomat any position(s) may be bonded to one or more group(s) selected fromthe substituent group B.

The substituent group B: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, formyl, imino, hydroxyimino, cyanoimino,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D, alkylamino optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylimino optionally substituted with one or moregroup(s) selected from the substituent group D, alkyloxyimino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonyloxy optionally substituted with one ormore group(s) selected from the substituent group D, alkyloxycarbonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonyloxy optionally substituted with one ormore group(s) selected from the substituent group D, alkyloxysulfonyloptionally substituted with one or more group(s) selected from thesubstituent group D, aromatic carbocyclyl optionally substituted withone or more group(s) selected from the substituent group E, non-aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group E, aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclyl optionally substituted with one ormore group(s) selected from the substituent group E, aromaticcarbocyclyloxy optionally substituted with one or more group(s) selectedfrom the substituent group E, non-aromatic carbocyclyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclyloxy optionally substituted with one ormore group(s) selected from the substituent group E, non-aromaticheterocyclyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylsulfanyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticheterocyclylsulfanyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylaminooptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylamino optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylamino optionally substituted with one ormore group(s) selected from the substituent group E, non-aromaticheterocyclylamino optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylcarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylcarbonyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticheterocyclylcarbonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylsulfonyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticheterocyclylsulfonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylcarbonylaminooptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylcarbonylamino optionally substituted withone or more group(s) selected from the substituent group E, non-aromaticheterocyclylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticcarbocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticcarbocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticheterocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticcarbocyclylcarbamoyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic carbocyclylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclylcarbamoyl optionally substituted withone or more group(s) selected from the substituent group E, aromaticcarbocyclylsulfamoyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic carbocyclylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclylsulfamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclylsulfamoyl optionally substituted withone or more group(s) selected from the substituent group E, aromaticcarbocyclyloxycarbonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromaticcarbocyclyloxycarbonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclyloxycarbonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclyloxycarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclyloxysulfonyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclyloxysulfonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclyloxysulfonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclyloxysulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclylcarbonyloxy optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclylcarbonyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclylcarbonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclylcarbonyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclylsulfonyloxy optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclylsulfonyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclylsulfonyloxyoptionally substituted with one or more group(s) selected from the substituent group E, and non-aromatic heterocyclylsulfonyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E.

The substituents on the rings of “aromatic carbocycle”, “non-aromaticcarbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of“substituted or unsubstituted 5-membered non-aromatic heterocycle” and“substituted or unsubstituted 6-membered non-aromatic heterocycle”,“substituted or unsubstituted aromatic carbocycle”, “substituted orunsubstituted non-aromatic carbocycle”, “substituted or unsubstitutedaromatic heterocycle”, and “substituted or unsubstituted non-aromaticheterocycle”, “substituted or unsubstituted 6-membered aromaticcarbocycle”, “substituted or unsubstituted 5- to 6-membered non-aromaticcarbocycle”, “substituted or unsubstituted 5- to 6-membered aromaticheterocycle”, and “substituted or unsubstituted 5- to 6-memberednon-aromatic heterocycle”, “substituted or unsubstituted aromaticcarbocyclyl”, “substituted or unsubstituted non-aromatic carbocyclyl”,“substituted or unsubstituted aromatic heterocyclyl”, and “substitutedor unsubstituted non-aromatic heterocyclyl”, “substituted orunsubstituted 6-membered aromatic carbocyclyl”, “substituted orunsubstituted 3- to 6-membered non-aromatic carbocyclyl”, “substitutedor unsubstituted 5- to 6-membered aromatic heterocyclyl”, and“substituted or unsubstituted 5- to 6-membered non-aromaticheterocyclyl”, “substituted or unsubstituted aromatic carbocyclyl”,“substituted or unsubstitute d non-aromatic carbocyclyl”, “substitutedor unsubstituted aromatic heterocyclyl”, and “substituted orunsubstituted non-aromatic heterocyclyl”, “substituted or unsubstitutedaromatic carbocyclyloxy”, “substituted or unsubstituted non-aromaticcarbocyclyloxy”, “substituted or unsubstituted aromaticheterocyclyloxy”, and “substituted or unsubstituted non-aromaticheterocyclyloxy”, “substituted or unsubstituted aromaticcarbocyclylamino”, “substituted or unsubstituted non-aromaticcarbocyclylamino”, “substituted or unsubstituted aromaticheterocyclylamino”, and “substituted or unsubstituted non-aromaticheterocyclylamino”, “substituted or unsubstituted aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted aromaticheterocyclylsulfanyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfanyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted aromaticheterocyclylcarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted aromaticheterocyclylsulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted aromaticheterocyclylcarbonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted aromaticheterocyclyloxycarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted aromaticheterocyclylsulfonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted aromaticheterocyclyloxysulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted aromaticheterocyclylcarbamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbamoyl”, “substituted or unsubstituted aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted aromaticheterocyclylsulfamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfamoyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted aromaticheterocyclylcarbonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylcarbonylamino”, “substituted or unsubstitutedaromatic carbocyclylsulfonylamino”, “substituted or unsubstitutednon-aromatic carbocyclylsulfonylamino”, “substituted or unsubstitutedaromatic heterocyclylsulfonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylsulfonylamino”, and “substituted orunsubstituted aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted non-aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted aromatic heterocyclyloxycarbonylamino”, and “substitutedor unsubstituted non-aromatic heterocyclyloxycarbonylamino” include thesubstituent group C1. An atom at any position(s) on the ring may bebonded to one or more group(s) selected from the substituent group C1.

The substituent group C1: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, alkyl optionally substituted with one or moregroup(s) selected from the substituent group D, alkenyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkynyl optionally substituted with one or more group(s)selected from the substituent group D, alkyloxy optionally substitutedwith one or more group(s) selected from the substituent group D,alkenyloxy optionally substituted with one or more group(s) selectedfrom the substituent group D, alkynyloxy optionally substituted with oneor more group(s) selected from the substituent group D, alkylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkenylamino optionally substituted with one ormore group(s) selected from the substituent group D, alkynylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfanyl optionally substituted with one ormore group(s) selected from the substituent group D, alkenylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkynylsulfanyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonylamino optionally substituted with oneor more group(s) selected from the substituent group D, alkylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxycarbonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxysulfonyl optionally substituted with one ormore group(s) selected from the substituent group D, aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group E, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group E, aromatic carbocyclyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic carbocyclyloxy optionally substituted with one ormore group(s) selected from the substituent group E, aromaticheterocyclyloxy optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylsulfanyl optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylsulfanyl optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfanyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylamino optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylamino optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylaminooptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylcarbonyl optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylcarbonyl optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylcarbonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylsulfonyl optionally substitutedwith one or more group(s) selected from the substituent group E,non-aromatic carbocyclylsulfonyl optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic heterocyclylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic carbocyclylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic carbocyclylcarbonylamino optionally substitutedwith one or more group(s) selected from the substituent group E,aromatic heterocyclylcarbonylamino optionally substituted with one ormore group(s) selected from the substituent group E, non-aromaticheterocyclylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticcarbocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticcarbocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticheterocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, non-aromaticheterocyclylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group E, aromaticcarbocyclylcarbamoyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic carbocyclylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclylcarbamoyl optionally substituted withone or more group(s) selected from the substituent group E, aromaticcarbocyclylsulfamoyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromatic carbocyclylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group E, aromatic heterocyclylsulfamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclylsulfamoyl optionally substituted withone or more group(s) selected from the substituent group E, aromaticcarbocyclyloxycarbonyl optionally substituted with one or more group(s)selected from the substituent group E, non-aromaticcarbocyclyloxycarbonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclyloxycarbonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclyloxycarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclyloxysulfonyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclyloxysulfonyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclyloxysulfonyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclyloxysulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclylcarbonyloxy optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclylcarbonyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclylcarbonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic heterocyclylcarbonyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic carbocyclylsulfonyloxy optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticcarbocyclylsulfonyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic heterocyclylsulfonyloxyoptionally substituted with one or more group(s) selected from thesubstituent group E, and non-aromatic heterocyclylsulfonyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E.

The substituent group C2: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, alkyloxy, haloalkyloxy, alkylamino,haloalkylamino, alkylsulfanyl, haloalkylsulfanyl, and aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group F, and non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F.

The substituent group D: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, alkyloxy, non-aromatic carbocyclyl, andalkylsulfonyl.

The substituent group E: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, and cyano, and alkyl optionally substituted with oneor more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonyloxy optionally substituted with one ormore group(s) selected from the substituent group D, alkyloxycarbonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonyloxy optionally substituted with one ormore group(s) selected from the substituent group D, andalkyloxysulfonyl optionally substituted with one or more group(s)selected from the substituent group D.

The substituent group F: halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy,alkylamino, haloalkylamino, alkylsulfanyl, haloalkylsulfanyl,alkylcarbonyl, haloalkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl,alkylcarbonylamino, haloalkylcarbonylamino, alkylsulfonylamino, haloalkylsulfonylamino, alkylcarbamoyl, haloalkylcarbamoyl, alkylsulfamoyl,and haloalkylsulfamoyl.

“Substituted or unsubstituted non-aromatic carbocyclyl” and “substitutedor unsubstituted non-aromatic heterocyclyl” may be optionallysubstituted with one or more “oxo”. In this case, it means a groupwherein two hydrogen atoms on a carbon atom are replaced as below.

The non-aromatic carbocycle or non-aromatic heterocycle part of theabove “non-aromatic carbocyclyloxy”, “non-aromatic carbocyclylamino”,“non-aromatic carbocyclylsulfanyl”, “non-aromatic carbocyclylcarbonyl”,“non-aromatic carbocyclylsulfonyl”, “non-aromaticcarbocyclylcarbonyloxy”, “non-aromatic carbocyclylsulfonyloxy”,“non-aromatic carbocyclyloxycarbonyl”, “non-aromaticcarbocyclyloxysulfonyl”, “non-aromatic carbocyclylcarbamoyl”,“non-aromatic carbocyclylsulfamoyl”, “non-aromaticcarbocyclylcarbonylamino”, “non-aromatic carbocyclylsulfonylamino”,“non-aromatic carbocyclyloxycarbonylamino”, “non-aromaticheterocyclyloxy”, “non-aromatic heterocyclylamino”, “non-aromaticheterocyclylsulfanyl”, “non-aromatic heterocyclylcarbonyl”,“non-aromatic heterocyclylsulfonyl”, “non-aromaticheterocyclylcarbonyloxy”, “non-aromatic heterocyclylsulfonyloxy”,“non-aromatic heterocyclyloxycarbonyl”, “non-aromaticheterocyclyloxysulfonyl”, “non-aromatic heterocyclylcarbamoyl”,“non-aromatic heterocyclylsulfamoyl”, “non-aromaticheterocyclylcarbonylamino”, “non-aromatic heterocyclylsulfonylamino”,and “non-aromatic heterocyclyloxycarbonylamino” may be optionallysubstituted with one or more “oxo” as above.

The substituents on the rings of “substituted or unsubstituted aromaticcarbocyclyl”, “substituted or unsubstituted non-aromatic carbocyclyl”,“substituted or unsubstituted aromatic heterocyclyl”, “substituted orunsubstituted non-aromatic heterocyclyl”, “substituted or unsubstituted6-membered aromatic carbocyclyl”, “substituted or unsubstituted 3- to6-membered non-aromatic carbocyclyl”, “substituted or unsubstituted 5-to 6-membered aromatic heterocyclyl”, and “substituted or unsubstituted5- to 6-membered non-aromatic heterocyclyl” in R¹ include, for example,halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano,alkyl optionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfamoyl optionally substituted with one ormore group(s) selected from the substituent group D and the like.

One embodiment is, for example, halogen, hydroxy, cyano, alkyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D or thelike.

One embodiment is, for example, halogen, alkyl, haloalkyl or the like.

One embodiment is, for example, halogen, alkyl or the like.

One embodiment is, for example, halogen or the like.

The substituents of “substituted or unsubstituted alkyl”, and“substituted or unsubstituted alkyloxy” in R^(2a′), R^(2b′), R^(2b),R^(2c), R^(2d), R^(8a) and R^(8b) include, for example, halogen,hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, aromatic carbocyclyl optionally substituted withone or more group(s) selected from the substituent group F, non-aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic heterocyclyl optionally substituted with one ormore group(s) selected from the substituent group F and the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

The substituents of “substituted or unsubstituted alkyl”, and“substituted or unsubstituted alkylcarbonyl” in R^(7a) include, forexample, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo,cyano, alkyloxy optionally substituted with one or more group(s)selected from the substituent group D, alkylamino optionally substitutedwith one or more group(s) selected from the substituent group D,alkylsulfanyl optionally substituted with one or more group(s) selectedfrom the substituent group D, alkylcarbonyl optionally substituted withone or more group(s) selected from the substituent group D,alkylsulfonyl optionally substituted with one or more group(s) selectedfrom the substituent group D, alkylcarbonylamino optionally substitutedwith one or more group(s) selected from the substituent group D,alkylsulfonylamino optionally substituted with one or more group(s)selected from the substituent group D, aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic carbocyclyl optionally substituted with one ormore group(s) selected from the substituent group F, aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F and the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylamino”, “substituted or unsubstitutedalkynylamino”, and “substituted or unsubstituted alkynylamino” in R⁴include, for example, halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, alkyloxy optionally substituted with one ormore group(s) selected from the substituent group D, alkylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfanyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonylamino optionally substituted with oneor more group(s) selected from the substituent group D, aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group F, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F and the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkynyloxy”, and “substituted or unsubstituted alkynyloxy” in R⁶include, for example, halogen, hydroxy, carboxy, amino, carbamoyl,sulfamoyl, sulfo, cyano, alkyloxy optionally substituted with one ormore group(s) selected from the substituent group D, alkylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfanyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonylamino optionally substituted with oneor more group(s) selected from the substituent group D, aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group F, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F and the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

The substituents on the rings of “substituted or unsubstituted aromaticcarbocyclyl”, “substituted or unsubstituted non-aromatic carbocyclyl”,“substituted or unsubstituted aromatic heterocyclyl”, and “substitutedor unsubstituted non-aromatic heterocyclyl” in R⁶ include, for example,halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano,alkyl optionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfamoyl optionally substituted with one ormore group(s) selected from the substituent group D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylamino”, “substituted or unsubstitutedalkenylamino”, “substituted or unsubstituted alkynylamino”, “substitutedor unsubstituted alkylcarbonyl”, “substituted or unsubstitutedalkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”,“substituted or unsubstituted alkylsulfonyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstitutedalkynylsulfonyl”, “substituted or unsubstituted alkylcarbonyloxy”,“substituted or unsubstituted alkenylcarbonyloxy”, “substituted orunsubstituted alkynylcarbonyloxy”, “substituted or unsubstitutedalkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”,“substituted or unsubstituted alkynyloxycarbonyl”, “substituted orunsubstituted alkylsulfonyloxy”, “substituted or unsubstitutedalkenylsulfonyloxy”, “substituted or unsubstituted alkynylsulfonyloxy”,“substituted or unsubstituted alkyloxysulfonyl”, “substituted orunsubstituted alkenyloxysulfonyl”, “substituted or unsubstitutedalkynyloxysulfonyl”, “substituted or unsubstituted alkylcarbamoyl”,“substituted or unsubstituted alkenylcarbamoyl”, “substituted orunsubstituted alkynylcarbamoyl”, “substituted or unsubstitutedalkylsulfamoyl”, “substituted or unsubstituted alkenylsulfamoyl”,“substituted or unsubstituted alkynylsulfamoyl”, “substituted orunsubstituted alkylcarbonylamino”, “substituted or unsubstitutedalkenylcarbonylamino”, “substituted or unsubstitutedalkynylcarbonylamino”, “substituted or unsubstitutedalkylsulfonylamino”, “substituted or unsubstitutedalkenylsulfonylamino”, “substituted or unsubstitutedalkyloxycarbonylamino”, “substituted or unsubstitutedalkenyloxycarbonylamino”, and “substituted or unsubstitutedalkynyloxycarbonylamino” in R^(5a), R^(5a′) and R^(5b) include halogen,hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, aromatic carbocyclyl optionally substituted withone or more group(s) selected from the substituent group F, non-aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic heterocyclyl optionally substituted with one ormore group(s) selected from the substituent group F, aromaticcarbocyclyloxy optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyloxy optionally substituted with one ormore group(s) selected from the substituent group F, non-aromaticheterocyclyloxy optionally substituted with one or more group(s)selected from the substituent group F, aromatic carbocyclylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group F, non-aromatic carbocyclylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclylsulfanyl optionally substituted with oneor more group(s) selected from the substituent group F, non-aromaticheterocyclylsulfanyl optionally substituted with one or more group(s)selected from the substituent group F, aromatic carbocyclylaminooptionally substituted with one or more group(s) selected from thesubstituent group F, non-aromatic carbocyclylamino optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclylamino optionally substituted with one ormore group(s) selected from the substituent group F, and non-aromaticheterocyclylamino optionally substituted with one or more group(s)selected from the substituent group F and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyloxy optionally substituted withone or more group(s) selected from the substituent group D, alkylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfanyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylcarbonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfonylamino optionally substituted with oneor more group(s) selected from the substituent group D, aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group F, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F or the like.

One embodiment is, for example, halogen, hydroxy, cyano, aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group F, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F or the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

One embodiment is, for example, hydroxy or the like.

The substituents on the rings of “aromatic carbocycle”, “non-aromaticcarbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of“substituted or unsubstituted aromatic carbocyclyl”, “substituted orunsubstituted non-aromatic carbocyclyl”, “substituted or unsubstitutedaromatic heterocyclyl”, “substituted or unsubstituted non-aromaticheterocyclyl”,

“substituted or unsubstituted aromatic carbocyclyloxy”, “substituted orunsubstituted non-aromatic carbocyclyloxy”, “substituted orunsubstituted aromatic heterocyclyloxy”, “substituted or unsubstitutednon-aromatic heterocyclyloxy”,

“substituted or unsubstituted aromatic carbocyclylamino”, “substitutedor unsubstituted non-aromatic carbocyclylamino”, “substituted orunsubstituted aromatic heterocyclylamino”, “substituted or unsubstitutednon-aromatic heterocyclylamino”,

“substituted or unsubstituted aromatic carbocyclylsulfanyl”,“substituted or unsubstituted non-aromatic carbocyclylsulfanyl”,“substituted or unsubstituted aromatic heterocyclylsulfanyl”,“substituted or unsubstituted non-aromatic heterocyclylsulfanyl”,

“substituted or unsubstituted aromatic carbocyclylcarbonyl”,“substituted or unsubstituted non-aromatic carbocyclylcarbonyl”,“substituted or unsubstituted aromatic heterocyclylcarbonyl”,“substituted or unsubstituted non-aromatic heterocyclylcarbonyl”,

“substituted or unsubstituted aromatic carbocyclylsulfonyl”,“substituted or unsubstituted non-aromatic carbocyclylsulfonyl”,“substituted or unsubstituted aromatic heterocyclylsulfonyl”,“substituted or unsubstituted non-aromatic heterocyclylsulfonyl”,

“substituted or unsubstituted aromatic carbocyclylcarbonyloxy”,“substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy”,“substituted or unsubstituted aromatic heterocyclylcarbonyloxy”,“substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy”,

“substituted or unsubstituted aromatic carbocyclyloxycarbonyl”,“substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl”,“substituted or unsubstituted aromatic heterocyclyloxycarbonyl”,“substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl”,

“substituted or unsubstituted aromatic carbocyclylsulfonyloxy”,“substituted or unsubstituted non-aromatic carbocyclylsulfonyloxy”,“substituted or unsubstituted aromatic heterocyclylsulfonyloxy”,“substituted or unsubstituted non-aromatic heterocyclylsulfonyloxy”,“substituted or unsubstituted aromatic carbocyclyloxysulfonyl”,“substituted or unsubstituted non-aromatic carbocyclyloxysulfonyl”,“substituted or unsubstituted aromatic heterocyclyloxysulfonyl”,“substituted or unsubstituted non-aromatic heterocyclyloxysulfonyl”,

“substituted or unsubstituted aromatic carbocyclylcarbamoyl”,“substituted or unsubstituted non-aromatic carbocyclylcarbamoyl”,“substituted or unsubstituted aromatic heterocyclylcarbamoyl”,“substituted or unsubstituted non-aromatic heterocyclylcarbamoyl”,

“substituted or unsubstituted aromatic carbocyclylsulfamoyl”,“substituted or unsubstituted non-aromatic carbocyclylsulfamoyl”,“substituted or unsubstituted aromatic heterocyclylsulfamoyl”,“substituted or unsubstituted non-aromatic heterocyclylsulfamoyl”,

“substituted or unsubstituted aromatic carbocyclylcarbonylamino”,“substituted or unsubstituted non-aromatic carbocyclylcarbonylamino”,“substituted or unsubstituted aromatic heterocyclylcarbonylamino”,“substituted or unsubstituted non-aromatic heterocyclylcarbonylamino”,

“substituted or unsubstituted aromatic carbocyclylsulfonylamino”,“substituted or unsubstituted non-aromatic carbocyclylsulfonylamino”,“substituted or unsubstituted aromatic heterocyclylsulfonylamino”,“substituted or unsubstituted non-aromatic heterocyclylsulfonylamino”,

“substituted or unsubstituted aromatic carbocyclyloxycarbonylamino”,“substituted or unsubstituted non-aromatic carbocyclyloxycarbonylamino”,“substituted or unsubstituted aromatic heterocyclyloxycarbonylamino”,and “substituted or unsubstituted non-aromaticheterocyclyloxycarbonylamino” in R^(5a), R^(5a′), and R^(5b) include,for example, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl,sulfo, cyano, alkyl optionally substituted with one or more group(s)selected from the substituent group D, alkyloxy optionally substitutedwith one or more group(s) selected from the substituent group D,alkylamino optionally substituted with one or more group(s) selectedfrom the substituent group D, alkylsulfanyl optionally substituted withone or more group(s) selected from the substituent group D,alkylcarbonyl optionally substituted with one or more group(s) selectedfrom the substituent group D, alkylsulfonyl optionally substituted withone or more group(s) selected from the substituent group D,alkylcarbonylamino optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbamoyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

The substituents on the rings of “substituted or unsubstituted5-membered non-aromatic heterocycle”, “substituted or unsubstituted5-membered aromatic heterocycle”, and “substituted or unsubstituted6-membered non-aromatic heterocycle” in Ring Q include, for example,halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano,alkyl optionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfamoyl optionally substituted with one ormore group(s) selected from the substituent group D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

One embodiment is, for example, alkyl or the like.

The substituents on the rings of “substituted or unsubstituted aromaticcarbocyclyl”, “substituted or unsubstituted aromatic heterocyclyl”,“substituted or unsubstituted non-aromatic carbocyclyl”, and“substituted or unsubstituted non-aromatic heterocyclyl” in R³ include,for example, halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl,sulfo, cyano, formyl, oxo, alkyl optionally substituted with one or moregroup(s) selected from the substituent group D, alkyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylamino optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, aromatic carbocyclyl optionally substituted withone or more group(s) selected from the substituent group E, non-aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group E, aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, non-aromatic heterocyclyl optionally substituted with one ormore group(s) selected from the substituent group E, aromaticcarbocyclyloxy optionally substituted with one or more group(s) selectedfrom the substituent group E, non-aromatic carbocyclyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclyloxy optionally substituted with one ormore group(s) selected from the substituent group E, non-aromaticheterocyclyloxy optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylsulfanyl optionally substituted with oneor more group(s) selected from the substituent group E, non-aromaticheterocyclylsulfanyl optionally substituted with one or more group(s)selected from the substituent group E, aromatic carbocyclylaminooptionally substituted with one or more group(s) selected from thesubstituent group E, non-aromatic carbocyclylamino optionallysubstituted with one or more group(s) selected from the substituentgroup E, aromatic heterocyclylamino optionally substituted with one ormore group(s) selected from the substituent group E, non-aromaticheterocyclylamino optionally substituted with one or more group(s)selected from the substituent group E and the like.

One embodiment is, for example, halogen, hydroxy, cyano, alkyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D or the like.

One embodiment is, for example, halogen, cyano, alkyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkyloxy optionally substituted with one or more group(s)selected from the substituent group D or the like.

One embodiment is, for example, halogen, cyano, alkyl, haloalkyl,alkyloxy, haloalkyloxy or the like.

One embodiment is, for example, halogen, cyano, substituted orunsubstituted alkyl (the substituent is hydroxy, halogen or alkyloxy),substituted or unsubstituted alkyloxy (the substituent is hydroxy,alkyloxy or halogen) or the like.

One embodiment is, for example, alkyl, cyano, halogen, hydroxyalkyl orhydroxyalkyloxy or the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylamino”, “substituted or unsubstitutedalkenylamino”, “substituted or unsubstituted alkynylamino”, “substitutedor unsubstituted alkylcarbonyl”, “substituted or unsubstitutedalkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”,“substituted or unsubstituted alkylsulfonyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstitutedalkynylsulfonyl”, “substituted or unsubstituted alkylcarbonyloxy”,“substituted or unsubstituted alkenylcarbonyloxy”, “substituted orunsubstituted alkynylcarbonyloxy”, “substituted or unsubstitutedalkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”,“substituted or unsubstituted alkynyloxycarbonyl”, “substituted orunsubstituted alkylsulfonyloxy”, “substituted or unsubstitutedalkenylsulfonyloxy”, “substituted or unsubstituted alkynylsulfonyloxy”,“substituted or unsubstituted alkyloxysulfonyl”, “substituted orunsubstituted alkenyloxysulfonyl”, “substituted or unsubstitutedalkynyloxysulfonyl”, “substituted or unsubstituted alkylcarbamoyl”,“substituted or unsubstituted alkenylcarbamoyl”, “substituted orunsubstituted alkynylcarbamoyl”, “substituted or unsubstitutedalkylsulfamoyl”, “substituted or unsubstituted alkenylsulfamoyl”,“substituted or unsubstituted alkynylsulfamoyl”, “substituted orunsubstituted alkylcarbonylamino”, “substituted or unsubstitutedalkenylcarbonylamino”, “substituted or unsubstitutedalkynylcarbonylamino”, “substituted or unsubstitutedalkylsulfonylamino”, “substituted or unsubstitutedalkenylsulfonylamino”, “substituted or unsubstitutedalkyloxycarbonylamino”, “substituted or unsubstitutedalkenyloxycarbonylamino”, and “substituted or unsubstitutedalkynyloxycarbonylamino” in R^(9a) and R^(9b) include, for example,halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D, alkylamino optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonylamino optionally substituted with oneor more group(s) selected from the substituent group D,alkylsulfonylamino optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfamoyl optionally substituted with one or more group(s)selected from the substituent group D, aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic carbocyclyl optionally substituted with one ormore group(s) selected from the substituent group F, aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyloxy optionally substituted withone or more group(s) selected from the substituent group D, alkylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfanyl optionally substituted with one ormore group(s) selected from the substituent group D, aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic heterocyclyl optionally substituted with one or moregroup(s) selected from the substituent group F, non-aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F or the like.

One embodiment is, for example, halogen, aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic carbocyclyl optionally substituted with one ormore group(s) selected from the substituent group F, aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F or the like.

One embodiment is, for example, halogen or the like.

The substituents on the rings of “aromatic carbocycle”, “non-aromaticcarbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of“substituted or unsubstituted aromatic carbocyclyl”, “substituted orunsubstituted non-aromatic carbocyclyl”, “substituted or unsubstitutedaromatic heterocyclyl”, and “substituted or unsubstituted non-aromaticheterocyclyl”, “substituted or unsubstituted aromatic carbocyclyloxy”,“substituted or unsubstituted non-aromatic carbocyclyloxy”, “substitutedor unsubstituted aromatic heterocyclyloxy”, and “substituted orunsubstituted non-aromatic heterocyclyloxy”, “substituted orunsubstituted aromatic carbocyclylamino”, “substituted or unsubstitutednon-aromatic carbocyclylamino”, “substituted or unsubstituted aromaticheterocyclylamino”, and “substituted or unsubstituted non-aromaticheterocyclylamino”, “substituted or unsubstituted aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted aromaticheterocyclylsulfanyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfanyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted aromaticheterocyclylcarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted aromaticheterocyclylsulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted aromaticheterocyclylcarbonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted aromaticheterocyclyloxycarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted aromaticheterocyclylsulfonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted aromaticheterocyclyloxysulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted aromaticheterocyclylcarbamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbamoyl”, “substituted or unsubstituted aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted aromaticheterocyclylsulfamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfamoyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted aromaticheterocyclylcarbonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylcarbonylamino”, “substituted or unsubstitutedaromatic carbocyclylsulfonylamino”, “substituted or unsubstitutednon-aromatic carbocyclylsulfonylamino”, “substituted or unsubstitutedaromatic heterocyclylsulfonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylsulfonylamino”, and “substituted orunsubstituted aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted non-aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted aromatic heterocyclyloxycarbonylamino”, and “substitutedor unsubstituted non-aromatic heterocyclyloxycarbonylamino” in R^(9a)and R^(9b) include, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D and the like.

One embodiment is, for example, halogen, hydroxy, cyano, alkyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylamino”, “substituted or unsubstitutedalkenylamino”, “substituted or unsubstituted alkynylamino”, “substitutedor unsubstituted alkylcarbonyl”, “substituted or unsubstitutedalkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”,“substituted or unsubstituted alkylsulfonyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstitutedalkynylsulfonyl”, “substituted or unsubstituted alkylcarbonyloxy”,“substituted or unsubstituted alkenylcarbonyloxy”, “substituted orunsubstituted alkynylcarbonyloxy”, “substituted or unsubstitutedalkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”,“substituted or unsubstituted alkynyloxycarbonyl”, “substituted orunsubstituted alkylsulfonyloxy”, “substituted or unsubstitutedalkenylsulfonyloxy”, “substituted or unsubstituted alkynylsulfonyloxy”,“substituted or unsubstituted alkyloxysulfonyl”, “substituted orunsubstituted alkenyloxysulfonyl”, “substituted or unsubstitutedalkynyloxysulfonyl”, “substituted or unsubstituted alkylcarbamoyl”,“substituted or unsubstituted alkenylcarbamoyl”, “substituted orunsubstituted alkynylcarbamoyl”, “substituted or unsubstitutedalkylsulfamoyl”, “substituted or unsubstituted alkenylsulfamoyl”,“substituted or unsubstituted alkynylsulfamoyl”, “substituted orunsubstituted alkylcarbonylamino”, “substituted or unsubstitutedalkenylcarbonylamino”, “substituted or unsubstitutedalkynylcarbonylamino”, “substituted or unsubstitutedalkylsulfonylamino”, “substituted or unsubstitutedalkenylsulfonylamino”, “substituted or unsubstitutedalkyloxycarbonylamino”, “substituted or unsubstitutedalkenyloxycarbonylamino”, and “substituted or unsubstitutedalkynyloxycarbonylamino” in R^(10a) and R^(10b) include, for example,halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D, alkylamino optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonylamino optionally substituted with oneor more group(s) selected from the substituent group D,alkylsulfonylamino optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfamoyl optionally substituted with one or more group(s)selected from the substituent group D, aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic carbocyclyl optionally substituted with one ormore group(s) selected from the substituent group F, aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, aromatic carbocyclyloxy optionally substituted with one or moregroup(s) selected from the substituent group F, non-aromaticcarbocyclyloxy optionally substituted with one or more group(s) selectedfrom the substituent group F, aromatic heterocyclyloxy optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic heterocyclyloxy optionally substituted with one ormore group(s) selected from the substituent group F, aromaticcarbocyclylsulfanyl optionally substituted with one or more group(s)selected from the substituent group F, non-aromatic carbocyclylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group F, aromatic heterocyclylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic heterocyclylsulfanyl optionally substituted withone or more group(s) selected from the substituent group F, aromaticcarbocyclylamino optionally substituted with one or more group(s)selected from the substituent group F, non-aromatic carbocyclylaminooptionally substituted with one or more group(s) selected from thesubstituent group F, aromatic heterocyclylamino optionally substitutedwith one or more group(s) selected from the substituent group F, andnon-aromatic heterocyclylamino optionally substituted with one or moregroup(s) selected from the substituent group F and the like.

One embodiment is, for example, halogen, hydroxy, cyano, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, aromatic carbocyclyl optionally substituted withone or more group(s) selected from the substituent group F, non-aromaticcarbocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic heterocyclyl optionally substituted with one ormore group(s) selected from the substituent group F or the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

One embodiment is, for example, hydroxy or the like.

The substituents on the rings of “aromatic carbocycle”, “non-aromaticcarbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of“substituted or unsubstituted aromatic carbocyclyl”, “substituted orunsubstituted non-aromatic carbocyclyl”, “substituted or unsubstitutedaromatic heterocyclyl”, and “substituted or unsubstituted non-aromaticheterocyclyl”, “substituted or unsubstituted aromatic carbocyclyloxy”,“substituted or unsubstituted non-aromatic carbocyclyloxy”, “substitutedor unsubstituted aromatic heterocyclyloxy”, and “substituted orunsubstituted non-aromatic heterocyclyloxy”, “substituted orunsubstituted aromatic carbocyclylamino”, “substituted or unsubstitutednon-aromatic carbocyclylamino”, “substituted or unsubstituted aromaticheterocyclylamino”, and “substituted or unsubstituted non-aromaticheterocyclylamino”, “substituted or unsubstituted aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted aromaticheterocyclylsulfanyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfanyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted aromaticheterocyclylcarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted aromaticheterocyclylsulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted aromaticheterocyclylcarbonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted aromaticheterocyclyloxycarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted aromaticheterocyclylsulfonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted aromaticheterocyclyloxysulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted aromaticheterocyclylcarbamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbamoyl”, “substituted or unsubstituted aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted aromaticheterocyclylsulfamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfamoyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted aromaticheterocyclylcarbonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylcarbonylamino”, “substituted or unsubstitutedaromatic carbocyclylsulfonylamino”, “substituted or unsubstitutednon-aromatic carbocyclylsulfonylamino”, “substituted or unsubstitutedaromatic heterocyclylsulfonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylsulfonylamino”, and “substituted orunsubstituted aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted non-aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted aromatic heterocyclyloxycarbonylamino”, and “substitutedor unsubstituted non-aromatic heterocyclyloxycarbonylamino” in R^(10a)and R^(10b) include, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

The substituents on the rings of “substituted or unsubstituted aromaticcarbocycle”, “substituted or unsubstituted non-aromatic carbocycle”,“substituted or unsubstituted aromatic heterocycle”, and “substituted orunsubstituted non-aromatic heterocycle” when “R^(9a) and R^(10a) whichare attached to the adjacent ring-constituting atoms, or R^(9b) andR^(10b) which are attached to the adjacent ring-constituting atoms aretaken together to form a substituted or unsubstituted aromaticcarbocycle, a substituted or unsubstituted non-aromatic carbocycle, asubstituted or unsubstituted aromatic heterocycle, or a substituted orunsubstituted non-aromatic heterocycle”, and the substituents on therings of “substituted or unsubstituted 5-membered non-aromaticcarbocycle”, “substituted or unsubstituted 5-membered aromaticheterocycle”, “substituted or unsubstituted 5-membered non-aromaticheterocycle”, “substituted or unsubstituted 6-membered aromaticcarbocycle”, “substituted or unsubstituted 6-membered non-aromaticcarbocycle”, “substituted or unsubstituted 6-membered aromaticheterocycle” and “substituted or unsubstituted 6-membered non-aromaticheterocycle” in Ring F3 and Ring G3 include, for example, halogen,hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D, alkylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfanyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbonylamino optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylcarbamoyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylsulfamoyl optionally substituted with one ormore group(s) selected from the substituent group D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

The substituents on the rings of “substituted or unsubstituted aromaticcarbocycle”, “substituted or unsubstituted non-aromatic carbocycle”,“substituted or unsubstituted aromatic heterocycle”, and “substituted orunsubstituted non-aromatic heterocycle” when “two R^(10a) which areattached to the adjacent ring-constituting atoms, or two R^(10b) whichare attached to the adjacent ring-constituting atoms are taken togetherto form a substituted or unsubstituted aromatic carbocycle, asubstituted or unsubstituted non-aromatic carbocycle, a substituted orunsubstituted aromatic heterocycle, or a substituted or unsubstitutednon-aromatic heterocycle”, and the substituents on the rings of“substituted or unsubstituted 5-membered non-aromatic carbocycle”,“substituted or unsubstituted 5-membered aromatic heterocycle”,“substituted or unsubstituted 5-membered non-aromatic heterocycle”,“substituted or unsubstituted 6-membered aromatic carbocycle”,“substituted or unsubstituted 6-membered non-aromatic carbocycle”,“substituted or unsubstituted 6-membered aromatic heterocycle” and“substituted or unsubstituted 6-membered non-aromatic heterocycle” inRing F1 and Ring G1 include, for example, halogen, hydroxy, carboxy,amino, carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D, alkylamino optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonylamino optionally substituted with oneor more group(s) selected from the substituent group D,alkylsulfonylamino optionally substituted with one or more group(s)selected from the substituent group D, alkylcarbamoyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylsulfamoyl optionally substituted with one or more group(s)selected from the substituent group D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

One embodiment is, for example, alkyl or the like.

The substituents of “substituted or unsubstituted alkyl”, “substitutedor unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”,“substituted or unsubstituted alkyloxy”, “substituted or unsubstitutedalkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted orunsubstituted alkylsulfanyl”, “substituted or unsubstitutedalkenylsulfanyl”, “substituted or unsubstituted alkynylsulfanyl”,“substituted or unsubstituted alkylamino”, “substituted or unsubstitutedalkenylamino”, “substituted or unsubstituted alkynylamino”, “substitutedor unsubstituted alkylcarbonyl”, “substituted or unsubstitutedalkenylcarbonyl”, “substituted or unsubstituted alkynylcarbonyl”,“substituted or unsubstituted alkylsulfonyl”, “substituted orunsubstituted alkenylsulfonyl”, “substituted or unsubstitutedalkynylsulfonyl”, “substituted or unsubstituted alkylcarbonyloxy”,“substituted or unsubstituted alkenylcarbonyloxy”, “substituted orunsubstituted alkynylcarbonyloxy”, “substituted or unsubstitutedalkyloxycarbonyl”, “substituted or unsubstituted alkenyloxycarbonyl”,“substituted or unsubstituted alkynyloxycarbonyl”, “substituted orunsubstituted alkylsulfonyloxy”, “substituted or unsubstitutedalkenylsulfonyloxy”, “substituted or unsubstituted alkynylsulfonyloxy”,“substituted or unsubstituted alkyloxysulfonyl”, “substituted orunsubstituted alkenyloxysulfonyl”, “substituted or unsubstitutedalkynyloxysulfonyl”, “substituted or unsubstituted alkylcarbamoyl”,“substituted or unsubstituted alkenylcarbamoyl”, “substituted orunsubstituted alkynylcarbamoyl”, “substituted or unsubstitutedalkylsulfamoyl”, “substituted or unsubstituted alkenylsulfamoyl”,“substituted or unsubstituted alkynylsulfamoyl”, “substituted orunsubstituted alkylcarbonylamino”, “substituted or unsubstitutedalkenylcarbonylamino”, “substituted or unsubstitutedalkynylcarbonylamino”, “substituted or unsubstitutedalkylsulfonylamino”, “substituted or unsubstitutedalkenylsulfonylamino”, “substituted or unsubstitutedalkyloxycarbonylamino”, “substituted or unsubstitutedalkenyloxycarbonylamino”, and “substituted or unsubstitutedalkynyloxycarbonylamino” in R^(10a1) and R^(10a2) include, for example,halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfo, cyano,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D, alkylamino optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfanyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfonyloptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbonylamino optionally substituted with oneor more group(s) selected from the substituent group D,alkylsulfonylamino optionally substituted with one or more group(s)selected from the substituent group D, aromatic carbocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F, non-aromatic carbocyclyl optionally substituted with one ormore group(s) selected from the substituent group F, aromaticheterocyclyl optionally substituted with one or more group(s) selectedfrom the substituent group F, non-aromatic heterocyclyl optionallysubstituted with one or more group(s) selected from the substituentgroup F and the like.

One embodiment is, for example, halogen, hydroxy, cyano or the like.

One embodiment is, for example, halogen or the like.

The substituents on the rings of “aromatic carbocycle”, “non-aromaticcarbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of“substituted or unsubstituted aromatic carbocyclyl”, “substituted orunsubstituted non-aromatic carbocyclyl”, “substituted or unsubstitutedaromatic heterocyclyl”, and “substituted or unsubstituted non-aromaticheterocyclyl”, “substituted or unsubstituted aromatic carbocyclyloxy”,“substituted or unsubstituted non-aromatic carbocyclyloxy”, “substitutedor unsubstituted aromatic heterocyclyloxy”, and “substituted orunsubstituted non-aromatic heterocyclyloxy”, “substituted orunsubstituted aromatic carbocyclylamino”, “substituted or unsubstitutednon-aromatic carbocyclylamino”, “substituted or unsubstituted aromaticheterocyclylamino”, and “substituted or unsubstituted non-aromaticheterocyclylamino”, “substituted or unsubstituted aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfanyl”, “substituted or unsubstituted aromaticheterocyclylsulfanyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfanyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyl”, “substituted or unsubstituted aromaticheterocyclylcarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyl”, “substituted or unsubstituted aromaticheterocyclylsulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy”, “substituted or unsubstituted aromaticheterocyclylcarbonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl”, “substituted or unsubstituted aromaticheterocyclyloxycarbonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl”, “substituted or unsubstituted aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy”, “substituted or unsubstituted aromaticheterocyclylsulfonyloxy”, and “substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy”, “substituted or unsubstituted aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl”, “substituted or unsubstituted aromaticheterocyclyloxysulfonyl”, and “substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl”, “substituted or unsubstituted aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl”, “substituted or unsubstituted aromaticheterocyclylcarbamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylcarbamoyl”, “substituted or unsubstituted aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl”, “substituted or unsubstituted aromaticheterocyclylsulfamoyl”, and “substituted or unsubstituted non-aromaticheterocyclylsulfamoyl”, “substituted or unsubstituted aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino”, “substituted or unsubstituted aromaticheterocyclylcarbonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylcarbonylamino”, “substituted or unsubstitutedaromatic carbocyclylsulfonylamino”, “substituted or unsubstitutednon-aromatic carbocyclylsulfonylamino”, “substituted or unsubstitutedaromatic heterocyclylsulfonylamino”, and “substituted or unsubstitutednon-aromatic heterocyclylsulfonylamino”, and “substituted orunsubstituted aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted non-aromatic carbocyclyloxycarbonylamino”, “substituted orunsubstituted aromatic heterocyclyloxycarbonylamino”, and “substitutedor unsubstituted non-aromatic heterocyclyloxycarbonylamino” in R^(10a1)and R^(10a2) include, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonyl optionally substituted with one or more group(s)selected from the substituent group D, alkylsulfonyl optionallysubstituted with one or more group(s) selected from the substituentgroup D, alkylcarbonylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfonylaminooptionally substituted with one or more group(s) selected from thesubstituent group D, alkylcarbamoyl optionally substituted with one ormore group(s) selected from the substituent group D, alkylsulfamoyloptionally substituted with one or more group(s) selected from thesubstituent group D and the like.

One embodiment is, for example, halogen, hydroxy, carboxy, amino,carbamoyl, sulfamoyl, sulfo, cyano, alkyl optionally substituted withone or more group(s) selected from the substituent group D, alkyloxyoptionally substituted with one or more group(s) selected from thesubstituent group D, alkylamino optionally substituted with one or moregroup(s) selected from the substituent group D, alkylsulfanyl optionallysubstituted with one or more group(s) selected from the substituentgroup D or the like.

One embodiment is, for example, halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D,alkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D or the like.

One aspect of the present invention is illustrated below.

Specific examples of each substituent in the compound represented byFormula

-   (I) or pharmaceutically acceptable salt thereof are shown below. All    combinations each selected from (a) to (v) are illustrated for the    compounds represented by Formula (I).-   (a) A compound according to the following (a-1) or a    pharmaceutically acceptable salt thereof.-   (a-1) The compound represented by formula (I) wherein X is    N(R^(7a)), or pharmaceutically acceptable salt thereof.-   (b) A compound according to any one of the following (b-1) or (b-2)    or a pharmaceutically acceptable salt thereof.-   (b-1) The compound of formula (I) or the above (a), wherein R^(7a)    is a hydrogen atom, or substituted or unsubstituted alkyl, or    pharmaceutically acceptable salt thereof.-   (b-2) The compound of formula (I) or the above (a), wherein R^(7a)    is a hydrogen atom, or pharmaceutically acceptable salt thereof.-   (c) A compound according to any one of the following (c-1) to (c-3)    or a pharmaceutically acceptable salt thereof.-   (c-1) The compound of formula (I) or the above (a) or (b), wherein    R^(8a) and R^(8b) are each independently a hydrogen atom, halogen or    substituted or unsubstituted alkyl, or pharmaceutically acceptable    salt thereof.-   (c-2) The compound of formula (I) or the above (a) or (b) wherein    R^(8a) and R^(8b) are each independently a hydrogen atom, or    halogen, or pharmaceutically acceptable salt thereof.-   (c-3) The compound of formula (I) or the above (a) or (b) wherein    each of R^(8a) and R^(8b) is a hydrogen atom, or pharmaceutically    acceptable salt thereof.-   (d) A compound according to the following (d-1) or (d-2) or a    pharmaceutically acceptable salt thereof.-   (d-1) The compound of any one of formula (I) and the above (a) to    (c), wherein n is 0, or pharmaceutically acceptable salt thereof.-   (d-2) The compound of any one of formula (I) and the above (a)    to (c) and (d-1), wherein m is 0,-   or pharmaceutically acceptable salt thereof.-   (e) A compound according to any one of the following (e-1) to (e-3),    or a pharmaceutically acceptable salt thereof.-   (e-1) The compound of any one of Formula (I) and the above (a) to    (d), wherein

R^(2a′) is a hydrogen atom, halogen, or substituted or unsubstitutedalkyl, or

R^(2a) and R^(2b) which are attached to the same carbon atom are takentogether to form oxo,

or pharmaceutically acceptable salt thereof.

-   (e-2) The compound of any one of Formula (I) and the above (a) to    (d), wherein

R^(2a′) is a hydrogen atom or halogen,

or pharmaceutically acceptable salt thereof.

-   (e-3) The compound of any one of Formula (I) and the above (a) to    (d), wherein

R^(2a′) is a hydrogen atom,

or pharmaceutically acceptable salt thereof.

-   (f) A compound according to any one of the following (f-1) to (f-3),    or a pharmaceutically acceptable salt thereof.-   (f-1) The compound of any one of Formula (I) and the above (a) to    (e), wherein

R^(2b′) is a hydrogen atom, halogen, or substituted or unsubstitutedalkyl, or

R^(2a) and R^(2b) which are attached to the same carbon atom are takentogether to form oxo,

or a pharmaceutically acceptable salt thereof.

-   (f-2) The compound of any one of Formula (I) and the above (a) to    (e), wherein

R^(2b′) is a hydrogen atom or halogen,

or a pharmaceutically acceptable salt thereof.

-   (f-3) The compound of any one of Formula (I) and the above (a) to    (e), wherein

R^(2b′) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (g) A compound according to any one of the following (g-1) to (g-3),    or a pharmaceutically acceptable salt thereof.-   (g-1) The compound of any one of Formula (I) and the above (a) to    (f), wherein

R^(2b) is a hydrogen atom, halogen, or substituted or unsubstitutedalkyl, or

R^(2a) and R^(2b) which are attached to the same carbon atom are takentogether to form oxo,

or a pharmaceutically acceptable salt thereof.

-   (g-2) The compound of any one of Formula (I) and the above (a) to    (f), wherein

R^(2b) is a hydrogen atom or halogen,

or a pharmaceutically acceptable salt thereof.

-   (g-3) The compound of any one of Formula (I) and the above (a) to    (f), wherein

R^(2b) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (h) A compound according to any one of the following (h-1) to (h-3),    or a pharmaceutically acceptable salt thereof.-   (h-1) The compound of any one of Formula (I) and the above (a) to    (g), wherein

R^(2′) is a hydrogen atom, halogen, or substituted or unsubstitutedalkyl,

or a pharmaceutically acceptable salt thereof.

-   (h-2) The compound of any one of Formula (I) and the above (a) to    (g), wherein

R^(2c) is a hydrogen atom or halogen,

or a pharmaceutically acceptable salt thereof.

-   (h-3) The compound of any one of Formula (I) and the above (a) to    (g), wherein

R^(2c) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (i) A compound according to any one of the following (i-1) to (i-3),    or a pharmaceutically acceptable salt thereof.-   (i-1) The compound of any one of Formula (I) and the above (a) to    (h), wherein

R^(2d) is a hydrogen atom, halogen, or substituted or unsubstitutedalkyl,

or a pharmaceutically acceptable salt thereof.

-   (i-2) The compound of any one of Formula (I) and the above (a) to    (h), wherein

R^(2d) is a hydrogen atom or halogen,

or a pharmaceutically acceptable salt thereof.

-   (i-3) The compound of any one of Formula (I) and the above (a) to    (h), wherein

R^(2d) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (j) A compound according to the following (j-1),    or a pharmaceutically acceptable salt thereof.-   (j-1) The compound of any one of Formula (I) and the above (a) to    (i), wherein

Y¹ is O,

or a pharmaceutically acceptable salt thereof.

-   (k) A compound according to any one of the following (k-1) to (k-3),    or a pharmaceutically acceptable salt thereof.-   (k-1) The compound of any one of Formula (I) and the above (a) to    (j), wherein

R⁴ is a hydrogen atom, halogen, or substituted or unsubstituted alkyl,

or a pharmaceutically acceptable salt thereof.

-   (k-2) The compound of any one of Formula (I) and the above (a) to    (j), wherein

R⁴ is a hydrogen atom or halogen,

or a pharmaceutically acceptable salt thereof.

-   (k-3) The compound of any one of Formula (I) and the above (a) to    (j), wherein

R⁴ is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (l) A compound according to the following (1-1) or (1-2),    or a pharmaceutically acceptable salt thereof.-   (l-1) The compound of any one of Formula (I) and the above (a) to    (k), wherein

R⁶ is a hydrogen atom, hydroxy, cyano, substituted or unsubstitutedalkyl, or substituted or unsubstituted alkyloxy,

or a pharmaceutically acceptable salt thereof.

-   (l-2) The compound of any one of Formula (I) and the above (a) to    (k), wherein

R⁶ is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (m) A compound according to any one of the following (m-1) to    (m-17),    or a pharmaceutically acceptable salt thereof.-   (m-1) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is substituted or unsubstituted 6-membered aromatic carbocyclyl,substituted or unsubstituted 3 to 6-membered non-aromatic carbocyclyl,substituted or unsubstituted 5- to 6-membered aromatic heterocyclyl, orsubstituted or unsubstituted 5- to 6-membered non-aromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (m-2) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is substituted or unsubstituted 6-membered aromatic carbocyclyl, orsubstituted or unsubstituted 5- to 6-membered aromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (m-3) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is substituted or unsubstituted phenyl,

or a pharmaceutically acceptable salt thereof.

-   (m-4) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is phenyl substituted with one or more group(s) selected from halogenand alkyl, or unsubstituted phenyl,

or a pharmaceutically acceptable salt thereof.

-   (m-5) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is 6-membered aromatic carbocyclyl substituted with one or morehalogen atom(s) and optionally substituted with one or more and same ordifferent substituent(s), or 5- to 6-membered aromatic heterocyclylsubstituted with one or more halogen atom(s) and optionally substitutedwith one or more and same or different substituent(s),

or a pharmaceutically acceptable salt thereof.

-   (m-6) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is phenyl substituted with one or more halogen atom(s) and optionallysubstituted with one or more and same or different substituent(s),

or a pharmaceutically acceptable salt thereof.

-   (m-7) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is phenyl substituted with one or more halogen atom(s),

or a pharmaceutically acceptable salt thereof.

-   (m-8) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is a group represented by the formula:

wherein

Ring E is a 6-membered aromatic carbocycle, a 6-membered non-aromaticcarbocycle, a 6-membered aromatic heterocycle, or a 6-memberednon-aromatic heterocycle;

R^(12a) and R^(13a) are each independently halogen;

R¹² and R¹³ are each independently a group selected from the substituentgroup C1;

q1 is an integer from 0 to 2; and

q2 is an integer from 0 to 2,

or a pharmaceutically acceptable salt thereof.

-   (m-9) The compound of the above (m-8), wherein

R¹² and R¹³ are each independently halogen, alkyl optionally substitutedwith one or more group(s) selected from the substituent group D, oralkyloxy optionally substituted with one or more group(s) selected fromthe substituent group D, or a pharmaceutically acceptable salt thereof.

-   (m-10) The compound of the above (m-8), wherein

R¹² and R¹³ are each independently halogen, alkyl, or haloalkyl,

or a pharmaceutically acceptable salt thereof.

-   (m-11) The compound of the above (m-8), wherein

R¹² and R¹³ are each independently halogen,

or a pharmaceutically acceptable salt thereof.

-   (m-12) The compound of any one of Formula (I) and the above (a) to    (1), wherein

R¹ is a group represented by the formula:

wherein

R^(12a) and R^(13a) are each independently halogen; and

R^(12b), R^(12c), and R^(13b) are each independently halogen, alkyloptionally substituted with one or more group(s) selected from thesubstituent group D, or alkyloxy optionally substituted with one or moregroup(s) selected from the substituent group D,

or a pharmaceutically acceptable salt thereof.

-   (m-13) The compound of the above (m-12), wherein

R^(12b), R^(12c), and R^(13b) are each independently halogen, or alkyloptionally substituted with one or more group(s) selected from thesubstituent group D,

or a pharmaceutically acceptable salt thereof.

-   (m-14) The compound of the above (m-12), wherein

R^(12b), R^(12c), and R^(13b) are each independently halogen, alkyl, orhaloalkyl, or a pharmaceutically acceptable salt thereof.

-   (m-15) The compound of the above (m-12), wherein

R^(12b), R^(12c), and R^(13b) are each independently halogen,

or a pharmaceutically acceptable salt thereof.

-   (m-16) The compound of any one of the above (m-7) to (m-15), wherein

Ring E is benzene or a 6-membered aromatic heterocycle,

or a pharmaceutically acceptable salt thereof.

-   (m-17) The compound of any one of the above (m-7) to (m-15), wherein

Ring E is benzene,

or a pharmaceutically acceptable salt thereof.

-   (m-18) The compound of the above (m-17), wherein

R^(12a), R^(12b), and R¹², are each independently halogen,

or a pharmaceutically acceptable salt thereof.

-   (n) A compound according to any one of the following (n-1) to    (n-14),    or a pharmaceutically acceptable salt thereof.-   (n-1) The compound according to any one of Formula (I) and the    above (a) to (m), wherein

Z¹ is N,

or a pharmaceutically acceptable salt thereof.

-   (n-2) The compound according to any one of Formula (I) and the    above (a) to (m), wherein

Z¹ is C(R⁴),

or a pharmaceutically acceptable salt thereof.

-   (n-3) The compound of any one of Formula (I), the above (a) to (m),    (n-1), and (n-2), wherein

the dashed line represents the presence of a bond,

or a pharmaceutically acceptable salt thereof.

-   (n-4) The compound of the above (n-3), wherein

or a pharmaceutically acceptable salt thereof.

-   (n-5) The compound according to the above (n-3) or (n-4), wherein

Ring Q is a substituted or unsubstituted 5-membered saturatedheterocycle or a substituted or unsubstituted 6-membered saturatedheterocycle,

or a pharmaceutically acceptable salt thereof.

-   (n-6) The compound according to the above (n-3) or (n-4), wherein

Ring Q is substituted or unsubstituted pyrrolidine, substituted orunsubstituted imidazolidine, substituted or unsubstituted oxazolidine,substituted or unsubstituted piperidine, substituted or unsubstitutedoxadian, substituted or unsubstituted hexahydropyrimidine, substitutedor unsubstituted morpholine, or substituted or unsubstituted piperazine,

or a pharmaceutically acceptable salt thereof.

-   (n-7) The compound according to the above (n-3) or (n-4), wherein

Ring Q is substituted or unsubstituted pyrrolidine, substituted orunsubstituted imidazolidine, substituted or unsubstituted oxazolidine,substituted or unsubstituted piperidine, substituted or unsubstitutedoxadian, or substituted or unsubstituted morpholine,

or a pharmaceutically acceptable salt thereof.

-   (n-8) The compound according to the above (n-3) or (n-4), wherein

Ring Q is unsubstituted pyrrolidine; imidazolidine substituted with oneor more group(s) selected from alkyl; unsubstituted imidazolidine;unsubstituted oxazolidine; unsubstituted piperidine; unsubstitutedoxadian; or unsubstituted morpholine,

or a pharmaceutically acceptable salt thereof.

-   (n-9) The compound of any one of Formula (I), the above (a) to (m),    (n-1) and (n-2), wherein

the dashed line represents the absence of a bond,

or a pharmaceutically acceptable salt thereof.

-   (n-10) The compound of the above (n-9), wherein

or a pharmaceutically acceptable salt thereof.

-   (n-11) The compound according to the above (n-9) or (n-10), wherein

Ring Q is substituted or unsubstituted dihydropyrrole, substituted orunsubstituted dihydroimidazole, substituted or unsubstitutedtetrahydropyrimidine, or substituted or unsubstitutedtetrahydropyrazine,

or a pharmaceutically acceptable salt thereof.

-   (n-12) The compound according to the above (n-9) or (n-10), wherein

Ring Q is substituted or unsubstituted dihydroimidazole,

or a pharmaceutically acceptable salt thereof.

-   (n-13) The compound according to the above (n-9) or (n-10), wherein

Ring Q is unsubstituted dihydroimidazole,

or a pharmaceutically acceptable salt thereof.

-   (n-14) The compound according to any one of the above Formula (I),    the above (a) to (m), (n-1), and (n-13), wherein

or a pharmaceutically acceptable salt thereof.

-   (o) A compound according to any one of the following (o-1) to    (o-10), or a pharmaceutically acceptable salt thereof.-   (o-1) The compound of any one of Formula (I) and the above (a) to    (n), wherein

R^(5a) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylsulfanyl, substituted or unsubstitutedalkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (o-2) The compound of any one of Formula (I) and the above (a) to    (n), wherein

R^(5a) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted aromatic carbocyclyl, or substituted or unsubstitutedaromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (o-3) The compound of any one of Formula (I) and the above (a) to    (n), wherein

R^(5a) is each independently halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted aromatic carbocyclyl, orsubstituted or unsubstituted aromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (o-4) The compound of any one of Formula (I) and the above (a) to    (n), wherein

R^(5a) is halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkyloxy, orsubstituted or unsubstituted aromatic carbocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (o-5) The compound of any one of Formula (I) and the above (a) to    (n), wherein

R^(5a) is halogen; unsubstituted alkyl; unsubstituted alkenyl;unsubstituted alkyloxy; or unsubstituted aromatic carbocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (o-6) The compound of any one of Formula (I), the above (a) to (n),    and the above (o-1) to (o-5), wherein

R^(5a′) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted aromatic carbocyclyl, or substituted or unsubstitutedaromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (o-7) The compound according to any one of Formula (I), the    above (a) to (n), and the above (o-1) to (o-5), wherein

R^(5a′) is a hydrogen atom,

or a pharmaceutically acceptable salt thereof.

-   (o-8) The compound according to any one of Formula (I), the    above (a) to (n), and the above (o-1) to (o-7), wherein

R^(5b) is a hydrogen atom, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, or substituted or unsubstitutedalkynyl, or a pharmaceutically acceptable salt thereof.

-   (o-9) The compound according to any one of Formula (I), the    above (a) to (n), and the above (o-1) to (o-7), wherein

R^(5b) is a hydrogen atom, or substituted or unsubstituted alkyl,

or a pharmaceutically acceptable salt thereof.

-   (o-10) The compound according to any one of Formula (I), the    above (a) to (n), and the above (o-1) to (o-7), wherein

R^(5b) is unsubstituted alkyl,

or a pharmaceutically acceptable salt thereof.

-   (p) A compound according to any one of the following (p-1) to (p-3),    or a pharmaceutically acceptable salt thereof.-   (p-1) The compound according to any one of Formula (I) and the    above (a) to (o), wherein

R³ is substituted or unsubstituted 6-membered aromatic carbocyclyl, orsubstituted or unsubstituted 6- to 10-membered aromatic heterocyclyl, ora pharmaceutically acceptable salt thereof.

-   (p-2) The compound according to any one of Formula (I) and the    above (a) to (o), wherein

R³ is substituted or unsubstituted 6-membered aromatic carbocyclyl,substituted or unsubstituted 6-membered aromatic heterocyclyl, orsubstituted or unsubstituted 9 to 10-membered aromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

-   (p-3) The compound according to any one of Formula (I) and the    above (a) to (o), wherein

R³ is substituted or unsubstituted phenyl, substituted or unsubstitutedpyridyl, substituted or unsubstituted pyrimidyl, substituted orunsubstituted pyrazyl, substituted or unsubstituted benzothiazolyl,substituted or unsubstituted dihydroisobenzofuranyl, or substituted orunsubstituted indolyl, or a pharmaceutically acceptable salt thereof.

-   (q) A compound according to any one of the following (q-1) to (q-12)    or a pharmaceutically acceptable salt thereof.-   (q-1) The compound of any one of formula (I) and the above (a) to    (p), wherein R³ is a group represented by the Formula:

wherein

Ring B is a 6-membered aromatic carbocycle, a 6-membered aromaticheterocycle, or a 6-membered non-aromatic heterocycle, Ring C is a5-membered aromatic heterocycle, R^(9a) and R^(9b) are eachindependently halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl,sulfo, cyano, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substitutedor unsubstituted alkynylsulfanyl, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkenylamino, substituted orunsubstituted alkynylamino, substituted or unsubstituted alkylcarbonyl,substituted or unsubstituted alkenylcarbonyl, substituted orunsubstituted alkynylcarbonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, substituted or unsubstitutedalkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy,substituted or unsubstituted alkynylcarbonyloxy, substituted orunsubstituted alkyloxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted alkylsulfonyloxy, substituted orunsubstituted alkenylsulfonyloxy, substituted or unsubstitutedalkynylsulfonyloxy, substituted or unsubstituted alkyloxysulfonyl,substituted or unsubstituted alkenyloxysulfonyl, substituted orunsubstituted alkynyloxysulfonyl, substituted or unsubstitutedalkylcarbamoyl, substituted or unsubstituted alkenylcarbamoyl,substituted or unsubstituted alkynylcarbamoyl, substituted orunsubstituted alkylsulfamoyl, substituted or unsubstitutedalkenylsulfamoyl, substituted or unsubstituted alkynylsulfamoyl,substituted or unsubstituted alkylcarbonylamino, substituted orunsubstituted alkenylcarbonylamino, substituted or unsubstitutedalkynylcarbonylamino, substituted or unsubstituted alkylsulfonylamino,substituted or unsubstituted alkenylsulfonylamino, substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl,substituted or unsubstituted aromatic carbocyclyloxy, substituted orunsubstituted non-aromatic carbocyclyloxy, substituted or unsubstitutedaromatic heterocyclyloxy, substituted or unsubstituted non-aromaticheterocyclyloxy, substituted or unsubstituted aromatic carbocyclylamino,substituted or unsubstituted non-aromatic carbocyclylamino, substitutedor unsubstituted aromatic heterocyclylamino, substituted orunsubstituted non-aromatic heterocyclylamino, substituted orunsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstitutednon-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

R^(10a) and R^(10b) are each independently halogen, hydroxy, carboxy,amino, carbamoyl, sulfamoyl, sulfo, cyano, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkyloxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted orunsubstituted alkenylsulfanyl, substituted or unsubstitutedalkynylsulfanyl, substituted or unsubstituted alkylamino, substituted orunsubstituted alkenylamino, substituted or unsubstituted alkynylamino,substituted or unsubstituted alkylcarbonyl, substituted or unsubstitutedalkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl,substituted or unsubstituted alkylcarbonyloxy, substituted orunsubstituted alkenylcarbonyloxy, substituted or unsubstitutedalkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl,substituted or unsubstituted alkenyloxycarbonyl, substituted orunsubstituted alkynyloxycarbonyl, substituted or unsubstitutedalkylsulfonyloxy, substituted or unsubstituted alkenylsulfonyloxy,substituted or unsubstituted alkynylsulfonyloxy, substituted orunsubstituted alkyloxysulfonyl, substituted or unsubstitutedalkenyloxysulfonyl, substituted or unsubstituted alkynyloxysulfonyl,substituted or unsubstituted alkylcarbamoyl, substituted orunsubstituted alkenylcarbamoyl, substituted or unsubstitutedalkynylcarbamoyl, substituted or unsubstituted alkylsulfamoyl,substituted or unsubstituted alkenylsulfamoyl, substituted orunsubstituted alkynylsulfamoyl, substituted or unsubstitutedalkylcarbonylamino, substituted or unsubstituted alkenylcarbonylamino,substituted or unsubstituted alkynylcarbonylamino, substituted orunsubstituted alkylsulfonylamino, substituted or unsubstitutedalkenylsulfonylamino, substituted or unsubstituted alkynylsulfonylamino,substituted or unsubstituted aromatic carbocyclyl, substituted orunsubstituted non-aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticheterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,substituted or unsubstituted non-aromatic carbocyclyloxy, substituted orunsubstituted aromatic heterocyclyloxy, substituted or unsubstitutednon-aromatic heterocyclyloxy, substituted or unsubstituted aromaticcarbocyclylamino, substituted or unsubstituted non-aromaticcarbocyclylamino, substituted or unsubstituted aromaticheterocyclylamino, substituted or unsubstituted non-aromaticheterocyclylamino, substituted or unsubstituted aromaticcarbocyclylsulfanyl, substituted or unsubstituted non-aromaticcarbocyclylsulfanyl, substituted or unsubstituted aromaticheterocyclylsulfanyl, substituted or unsubstituted non-aromaticheterocyclylsulfanyl, substituted or unsubstituted aromaticcarbocyclylcarbonyl, substituted or unsubstituted non-aromaticcarbocyclylcarbonyl, substituted or unsubstituted aromaticheterocyclylcarbonyl, substituted or unsubstituted non-aromaticheterocyclylcarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyl, substituted or unsubstituted non-aromaticcarbocyclylsulfonyl, substituted or unsubstituted aromaticheterocyclylsulfonyl, substituted or unsubstituted non-aromaticheterocyclylsulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted non-aromaticcarbocyclylcarbonyloxy, substituted or unsubstituted aromaticheterocyclylcarbonyloxy, substituted or unsubstituted non-aromaticheterocyclylcarbonyloxy, substituted or unsubstituted aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonyl, substituted or unsubstituted aromaticheterocyclyloxycarbonyl, substituted or unsubstituted non-aromaticheterocyclyloxycarbonyl, substituted or unsubstituted aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted non-aromaticcarbocyclylsulfonyloxy, substituted or unsubstituted aromaticheterocyclylsulfonyloxy, substituted or unsubstituted non-aromaticheterocyclylsulfonyloxy, substituted or unsubstituted aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted non-aromaticcarbocyclyloxysulfonyl, substituted or unsubstituted aromaticheterocyclyloxysulfonyl, substituted or unsubstituted non-aromaticheterocyclyloxysulfonyl, substituted or unsubstituted aromaticcarbocyclylcarbamoyl, substituted or unsubstituted non-aromaticcarbocyclylcarbamoyl, substituted or unsubstituted aromaticheterocyclylcarbamoyl, substituted or unsubstituted non-aromaticheterocyclylcarbamoyl, substituted or unsubstituted aromaticcarbocyclylsulfamoyl, substituted or unsubstituted non-aromaticcarbocyclylsulfamoyl, substituted or unsubstituted aromaticheterocyclylsulfamoyl, substituted or unsubstituted non-aromaticheterocyclylsulfamoyl, substituted or unsubstituted aromaticcarbocyclylcarbonylamino, substituted or unsubstituted non-aromaticcarbocyclylcarbonylamino, substituted or unsubstituted aromaticheterocyclylcarbonylamino, substituted or unsubstituted non-aromaticheterocyclylcarbonylamino, substituted or unsubstituted aromaticcarbocyclylsulfonylamino, substituted or unsubstituted non-aromaticcarbocyclylsulfonylamino, substituted or unsubstituted aromaticheterocyclylsulfonylamino, substituted or unsubstituted non-aromaticheterocyclylsulfonylamino, substituted or unsubstituted aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted non-aromaticcarbocyclyloxycarbonylamino, substituted or unsubstituted aromaticheterocyclyloxycarbonylamino, or substituted or unsubstitutednon-aromatic heterocyclyloxycarbonylamino;

p1 is an integer from 0 to 3; and

p2 is an integer from 0 to 2,

or pharmaceutically acceptable salt thereof.

-   (q-2) The compound of the above (q-1), wherein

R³ is a group represented by the formula:

or a pharmaceutically acceptable salt thereof.

-   (q-3) The compound of any one of the above (q-1) or (q-2), wherein    R^(10a) and R^(10b) are each independently halogen, hydroxy, amino,    carbamoyl, cyano, substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted alkyloxy, substituted or unsubstituted    alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or    unsubstituted alkylsulfanyl, substituted or unsubstituted    alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,    substituted or unsubstituted alkylamino, substituted or    unsubstituted alkenylamino, substituted or unsubstituted    alkynylamino, substituted or unsubstituted alkylcarbonyl,    substituted or unsubstituted alkenylcarbonyl, substituted or    unsubstituted alkynylcarbonyl, substituted or unsubstituted    alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl,    substituted or unsubstituted alkynylsulfonyl, substituted or    unsubstituted alkyloxycarbonyl, substituted or unsubstituted    alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,    substituted or unsubstituted aromatic carbocyclyl, substituted or    unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted    aromatic heterocyclyl, substituted or unsubstituted non-aromatic    heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy,    substituted or unsubstituted non-aromatic carbocyclyloxy,    substituted or unsubstituted aromatic heterocyclyloxy, or    substituted or unsubstituted non-aromatic heterocyclyloxy, or    pharmaceutically acceptable salt thereof.-   (q-4) The compound of the above (q-1) or (q-2), wherein

R^(10a) and R^(10b) are each independently halogen, cyano, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkyloxy, substituted or unsubstituted alkenyloxy, or substituted orunsubstituted alkynyloxy, or a pharmaceutically acceptable salt thereof.

-   (q-5) The compound of the above (q-1) or (q-2), wherein

R^(10a) and R^(10b) are each independently halogen, cyano, substitutedor unsubstituted alkyl, or substituted or unsubstituted alkyloxy,

or a pharmaceutically acceptable salt thereof.

-   (q-6) The compound of the above (q-1) or (q-2), wherein

R^(10a) and R^(10b) are each independently halogen; cyano; alkyl;haloalkyl; alkyloxy; haloalkyloxy, hydroxyalkyl, or hydroxyalkyloxy,

or a pharmaceutically acceptable salt thereof.

-   (q-7) The compound of any one of the above (q-1) to (q-6), wherein

p1 is 1 or 2,

or a pharmaceutically acceptable salt thereof.

-   (q-8) The compound of any one of the above (q-1) to (q-6), wherein

p1 is 2,

or a pharmaceutically acceptable salt thereof.

-   (q-9) The compound of any one of the above (q-1) to (q-6), wherein

p1 is 1,

or a pharmaceutically acceptable salt thereof.

-   (q-10) The compound of any one of the above (q-1) to (q-6), wherein

p1 is 0,

or a pharmaceutically acceptable salt thereof.

-   (q-11) The compound of any one of the above (q-1) to (q-10), wherein

p2 is 1,

or a pharmaceutically acceptable salt thereof.

-   (q-12) The compound of any one of the above (q-1) to (q-10), wherein

p2 is 0,

or a pharmaceutically acceptable salt thereof.

-   (q-13) The compound of the above (q-1), wherein

R^(10a) and R¹⁰ are each independently halogen; cyano; hydroxyalkyl; orhydroxyalkyloxy,

or a pharmaceutically acceptable salt thereof.

-   (q-14) The compound of the above (q-2), wherein

R^(10a) is each independently alkyloxy; cyano; halogen;alkyloxyalkyloxy; hydroxyalkyl; hydroxyalkyloxy; haloalkyloxy; oralkyloxyalkyl,

or a pharmaceutically acceptable salt thereof.

-   (q-15) The compound of the above (q-2), wherein

R^(10a) is each independently halogen; cyano; hydroxyalkyl; orhydroxyalkyloxy, or a pharmaceutically acceptable salt thereof.

-   (r) A compound according to any one of the following (r-1) to    (r-11),    or a pharmaceutically acceptable salt thereof.-   (r-1) The compound of any one of Formula (I) and the above (a) to    (p), wherein

R³ is a group represented by the formula:

wherein

Ring F1 is a substituted or unsubstituted 5-membered non-aromaticcarbocycle, a substituted or unsubstituted 5-membered aromaticheterocycle, or a substituted or unsubstituted 5-membered non-aromaticheterocycle,

Ring G1 is a substituted or unsubstituted 6-membered aromaticcarbocycle, a substituted or unsubstituted 6-membered non-aromaticcarbocycle, a substituted or unsubstituted 6-membered aromaticheterocycle, or a substituted or unsubstituted 6-membered non-aromaticheterocycle,

Ring B is a 6-membered aromatic carbocycle or a 6-membered aromaticheterocycle,

p1b is 0 or 1,

R^(9a) and R^(9b) are the same as the above (q-1); and

R^(10a1) is the same as R^(10a) of the above (q-1),

or a pharmaceutically acceptable salt thereof.

The above definition of R³ means that R^(10a1) is a substituent on RingB.

-   (r-2) The compound of any one of Formula (I) and the above (a) to    (p), wherein

R³ is a group represented by the formula:

or a pharmaceutically acceptable salt thereof.

-   (r-3) The compound of the above (r-1) or (r-2), wherein

Ring F1 is substituted or unsubstituted cyclopentene, substituted orunsubstituted furan, substituted or unsubstituted thiophene, substitutedor unsubstituted pyrrole, substituted or unsubstituted pyrazole,substituted or unsubstituted imidazole, substituted or unsubstitutedthiazole, substituted or unsubstituted oxazole, substituted orunsubstituted dihydrofuran, substituted or unsubstituteddihydrothiophene, substituted or unsubstituted dihydropyrrole, orsubstituted or unsubstituted dioxole,

or a pharmaceutically acceptable salt thereof.

-   (r-4) The compound of the above (r-1) or (r-2), wherein

Ring F1 is substituted or unsubstituted dihydrofuran, or substituted orunsubstituted thiazole,

or a pharmaceutically acceptable salt thereof.

-   (r-5) The compound of the above (r-1) or (r-2), wherein

Ring F1 is unsubstituted dihydrofuran; or thiazole substituted with oneor more group(s) selected from alkyl,

or a pharmaceutically acceptable salt thereof.

-   (r-6) The compound of any one of the above (r-1) to (r-5), wherein    Ring G1 is substituted or unsubstituted benzene, substituted or    unsubstituted cyclohexane, substituted or unsubstituted pyridine,    substituted or unsubstituted pyrazine, substituted or unsubstituted    pyrimidine, substituted or unsubstituted pyran, substituted or    unsubstituted dihydropyran, substituted or unsubstituted    dihydropyridine, substituted or unsubstituted tetrahydropyridine,    substituted or unsubstituted dihydropyrazine, substituted or    unsubstituted tetrahydropyrazine, substituted or unsubstituted    oxazine, substituted or unsubstituted dihydrooxazine, substituted or    unsubstituted dioxin, or substituted or unsubstituted dihydrodioxin,    or pharmaceutically acceptable salt thereof.-   (r-7) The compound of any one of the above (r-1) to (r-6), wherein    p1b is 0, or pharmaceutically acceptable salt thereof.-   (r-8) The compound of any one of the above (r-1) to (r-6), wherein    p1b is 1, or pharmaceutically acceptable salt thereof.-   (r-9) The compound of any one of the above (r-1) to (r-8), wherein    R^(10a1) is halogen, hydroxy, amino, carbamoyl, substituted or    unsubstituted alkyl, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl, substituted or unsubstituted    alkyloxy, substituted or unsubstituted alkenyloxy, substituted or    unsubstituted alkynyloxy, substituted or unsubstituted    alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl,    substituted or unsubstituted alkynylsulfanyl, substituted or    unsubstituted alkylamino, substituted or unsubstituted alkenylamino,    or substituted or unsubstituted alkynylamino, or pharmaceutically    acceptable salt thereof.-   (r-10) The compound of any one of the above (r-1) to (r-8), wherein    R^(10a1) is halogen, substituted or unsubstituted alkyl, or    substituted or unsubstituted alkyloxy, or pharmaceutically    acceptable salt thereof.-   (r-11) The compound of any one of the above (r-1) to (r-8), wherein    R^(10a′) is halogen, or pharmaceutically acceptable salt thereof.-   (s) A compound according to any one of the following (s-1) to (s-6)    or a pharmaceutically acceptable salt thereof.-   (s-1) The compound of any one of Formula (I) and the above (a) to    (r), wherein R^(9a) and R^(9b) are each independently halogen,    hydroxy, amino, substituted or unsubstituted alkyl, substituted or    unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted alkyloxy, substituted or unsubstituted    alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or    unsubstituted alkylsulfanyl, substituted or unsubstituted    alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl,    substituted or unsubstituted alkylamino, substituted or    unsubstituted alkenylamino, or substituted or unsubstituted    alkynylamino, or pharmaceutically acceptable salt thereof.-   (s-2) The compound according to any one of Formula (I) and the    above (a) to (r), wherein

R^(9a) and R^(9b) are each independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkyloxy, substitutedor unsubstituted alkylsulfanyl, or substituted or unsubstitutedalkylamino, or a pharmaceutically acceptable salt thereof.

-   (s-3) The compound of any one of Formula (I) and the above (a) to    (r), wherein R^(9a) and R^(9b) are each independently halogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, or substituted or unsubstituted alkynyl, or    pharmaceutically acceptable salt thereof.-   (s-4) The compound of any one of Formula (I) and the above (a) to    (r), wherein R^(9a) and R^(9b) are each independently substituted or    unsubstituted alkyl, or pharmaceutically acceptable salt thereof.-   (s-5) The compound of any one of Formula (I) and the above (a) to    (r), wherein R^(9a) and R^(9b) are each independently unsubstituted    alkyl, or pharmaceutically acceptable salt thereof.-   (s-6) The compound of any one of Formula (I) and the above (a) to    (r), wherein R^(9a) and R^(9b) are each independently unsubstituted    methyl or unsubstituted ethyl, or pharmaceutically acceptable salt    thereof.-   (s-7) The compound according to any one of Formula (I) and the    above (a) to (r), wherein-   R^(9a) and R^(9b) are each independently unsubstituted methyl, or a    pharmaceutically acceptable salt thereof.-   (s-8) The compound according to any one of Formula (I) and the    above (a) to (r), wherein-   R^(9a) is unsubstituted methyl,    or a pharmaceutically acceptable salt thereof.-   (t) A compound according to any one of the following (t-1) to (t-10)    or a pharmaceutically acceptable salt thereof.-   (t-1) The compound of any one of Formula (I) and the above (a) to    (p), wherein R³ is a group represented by the Formula:

wherein Ring F3 is a substituted or unsubstituted 5-memberednon-aromatic carbocycle, a substituted or unsubstituted 5-memberedaromatic heterocycle, or a substituted or unsubstituted 5-memberednon-aromatic heterocycle; Ring G3 is a substituted or unsubstituted6-membered aromatic carbocycle, a substituted or unsubstituted6-membered non-aromatic carbocycle, a substituted or unsubstituted6-membered aromatic heterocycle, or a substituted or unsubstituted6-membered non-aromatic heterocycle;

Ring B is a 6-membered aromatic carbocycle or a 6-membered aromaticheterocycle,

p1d is 0 or 1; and

R^(10a2) is the same as R^(10a) of the above (q-1),

or pharmaceutically acceptable salt thereof.

The above definition of R³ means that R^(10a1) is a substituent on RingB.

-   (t-2) The compound of the above (t-1), wherein Ring F3 is    substituted or unsubstituted cyclopentene, substituted or    unsubstituted furan, substituted or unsubstituted thiophene,    substituted or unsubstituted pyrrole, substituted or unsubstituted    pyrazole, substituted or unsubstituted imidazole, substituted or    unsubstituted thiazole, substituted or unsubstituted oxazole,    substituted or unsubstituted dihydrofuran, substituted or    unsubstituted dihydrothiophene, substituted or unsubstituted    dihydropyrrole, or substituted or unsubstituted dioxole,    or pharmaceutically acceptable salt thereof.-   (t-3) The compound of the above (t-1) or (t-2), wherein Ring G3 is    substituted or unsubstituted benzene, substituted or unsubstituted    cyclohexene, substituted or unsubstituted pyridine, substituted or    unsubstituted pyrazine, substituted or unsubstituted pyrimidine,    substituted or unsubstituted pyran, substituted or unsubstituted    dihydropyran, substituted or unsubstituted dihydropyridine,    substituted or unsubstituted tetrahydropyridine, substituted or    unsubstituted dihydropyrazine, substituted or unsubstituted    tetrahydropyrazine, substituted or unsubstituted oxazine,    substituted or unsubstituted dihydrooxazine, substituted or    unsubstituted dioxin, or substituted or unsubstituted dihydrodioxin,    or pharmaceutically acceptable salt thereof.-   (t-4) The compound of the above (t-1) or (t-2), wherein

Ring G3 is substituted or unsubstituted pyridine,

or a pharmaceutically acceptable salt thereof.

-   (t-5) The compound of any one of the above (t-1) or (t-2), wherein

Ring G3 is unsubstituted pyridine,

or a pharmaceutically acceptable salt thereof.

-   (t-6) The compound of any one of the above (t-1) to (t-5), wherein    p1d is 0, or pharmaceutically acceptable salt thereof.-   (t-7) The compound of any one of the above (t-1) to (t-5), wherein    p1d is 1, or pharmaceutically acceptable salt thereof.-   (t-8) The compound of any one of the above (t-1) to (t-7), wherein    R^(10a2) is halogen, hydroxy, amino, carbamoyl, substituted or    unsubstituted alkyl, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl, substituted or unsubstituted    alkyloxy, substituted or unsubstituted alkenyloxy, substituted or    unsubstituted alkynyloxy, substituted or unsubstituted    alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl,    substituted or unsubstituted alkynylsulfanyl, substituted or    unsubstituted alkylamino, substituted or unsubstituted alkenylamino,    or substituted or unsubstituted alkynylamino, or pharmaceutically    acceptable salt thereof.-   (t-9) The compound of any one of the above (t-1) to (t-7), wherein    R^(10a2) is halogen, substituted or unsubstituted alkyl, or    substituted or unsubstituted alkyloxy, or pharmaceutically    acceptable salt thereof.-   (t-10) The compound of any one of the above (t-1) to (t-7), wherein

R^(10a2) is halogen,

or a pharmaceutically acceptable salt thereof.

-   (u) A compound according to any one of the following (u-1) to (u-5),    or a pharmaceutically acceptable salt thereof.-   (u-1) The compound of any one of Formula (I) and the above (a) to    (t), wherein Ring B is benzene, cyclohexene, or a 6-membered    aromatic heterocycle, or    pharmaceutically acceptable salt thereof.-   (u-2) The compound of any one of Formula (I) and the above (a) to    (t), wherein Ring B is benzene, or a 6-membered aromatic    heterocycle, or pharmaceutically acceptable salt thereof.-   (u-3) The compound of any one of Formula (I) and the above (a) to    (t), wherein Ring B is benzene, pyridine, pyrimidine, or pyrazine,    or pharmaceutically acceptable salt thereof.-   (u-4) The compound of any one of Formula (I) and the above (a) to    (t), wherein Ring B is benzene, or pyridine, or pharmaceutically    acceptable salt thereof.-   (u-5) The compound of any one of Formula (I) and the above (a) to    (t), wherein Ring B is benzene, or pharmaceutically acceptable salt    thereof.-   (v) A compound according to any one of the following (v-1) to (v-4)    or a pharmaceutically acceptable salt thereof.-   (v-1) The compound of any one of Formula (I) and the above (a) to    (u), wherein Ring C is cyclopentane, or a 5-membered aromatic    heterocycle, or pharmaceutically acceptable salt thereof.-   (v-2) The compound of any one of Formula (I) and the above (a) to    (u), wherein Ring C is a 5-membered aromatic heterocycle, or    pharmaceutically acceptable salt thereof.-   (v-3) The compound of any one of Formula (I) and the above (a) to    (u), wherein

Ring C is pyrrole, pyrazole, or imidazole,

or a pharmaceutically acceptable salt thereof.

-   (v-4) The compound of any one of Formula (I) and the above (a) to    (u), wherein

Ring C is pyrazole,

or a pharmaceutically acceptable salt thereof.

The compounds represented by Formula (I) are not limited to specificisomers but include all possible isomers (e.g., keto-enol isomers,imine-enamine isomers, diastereoisomers, enantiomers, rotamers or thelike), racemates or mixtures thereof.

For example, a compound represented by Formula (I) wherein R^(7a) is ahydrogen atom includes the following tautomer.

When the dashed line represents the absence of a bond in the compoundrepresented by Formula (I), then a double bond is formed between carbonatoms adjacent to Z² and N and ring-constituting atoms of Ring Q towhich the carbon atoms are adjacent.

In the present specification, in a group represented by the Formula:

p1 hydrogen atom(s) which is attached to a ring-constituting atom onRing B can be replaced with R^(10a).

In the present specification, in a group represented by the Formula:

p2 hydrogen atom(s) which is attached to a ring-constituting atom onRing C can be replaced with R^(10b).

In the present specification, in a group represented by the Formula:

q1 hydrogen atom(s) which is attached to a ring-constituting atom onRing E can be replaced with R¹². q2 hydrogen atom(s) which is attachedto a ring-constituting atom on Ring E can be replaced with R¹³.

In the present specification, in a group represented by the Formula:

p1b hydrogen atom(s) which is attached to a ring-constituting atom onRing B can be replaced with R^(10a1).

In the present specification, in a group represented by the Formula:

p1d hydrogen atom(s) which is attached to a ring-constituting atom onRing B can be replaced with R^(10a2).

One or more hydrogen, carbon and/or other atoms in the compoundsrepresented by Formula (I) may be replaced with isotopes of hydrogen,carbon and/or other atoms respectively. Example s of isotopes includehydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodineand chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, ¹²³I and ³⁶C respectively. The compounds represented byFormula (I) include the compounds replaced with these isotopes. Thecompounds replaced with the above isotopes are useful as medicines andinclude all of radiolabeled compounds of the compound of Formula (I). A“method of radiolabeling” in the manufacture of the “radiolabeledcompounds” is encompassed by the present invention, and the“radiolabeled compounds” are useful for studies on metabolized drugpharmacokinetics, studies on binding assay and/or diagnostic tools.

A radiolabeled compound of the compounds represented by Formula (I) canbe prepared using well-known methods in the art. For example, atritium-labeled compound represented by Formula (I) can be prepared byintroducing a tritium to a certain compound represented by Formula (I),through a catalytic dehalogenation reaction using a tritium. This methodcomprises reacting with an appropriately-halogenated precursor of thecompound represented by Formula (I) with tritium gas in the presence ofan appropriate catalyst, such as Pd/C, and in the presence or absent ofa base. The other appropriate method of preparing a tritium-labeledcompound can be referred to “Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. A¹⁴C-labeled compound can be prepared by using a raw material having ¹⁴C.

The pharmaceutically acceptable salts of the compounds represented byFormula (I) include, for example, salts with alkaline metal (e.g.,lithium, sodium, potassium or the like), alkaline earth metal (e.g.,calcium, barium or the like), magnesium, transition metal (e.g., zinc,iron or the like), ammonia, organic bases (e.g., trimethylamine,triethylamine, dicyclohexylamine, ethanolamine, diethanolamine,triethanolamine, meglumine, ethylenediamine, pyridine, picoline,quinoline or the like) or amino acids, or salts with inorganic acids(e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid,hydrobromic acid, phosphoric acid, hydroiodic acid or the like) ororganic acids (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalicacid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malicacid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or thelike). Especially, salts with hydrochloric acid, sulfuric acid,phosphoric acid, tartaric acid, methanesulfonic acid and the like areincluded. These salts can be formed by the usual methods.

The compounds represented by Formula (I) of the present invention orpharmaceutically acceptable salts thereof may form solvates (e.g.,hydrates or the like) and/or crystal polymorphs. The present inventionencompasses those various solvates and crystal polymorphs. “Solvates”may be those wherein any numbers of solvent molecules (e.g., watermolecules or the like) are coordinated with the compounds represented byFormula (I). When the compounds represented by Formula (I) orpharmaceutically acceptable salts thereof are allowed to stand in theatmosphere, the compounds may absorb water, resulting in attachment ofadsorbed water or formation of hydrates. Recrystallization of thecompounds represented by Formula (I) or pharmaceutically acceptablesalts thereof may produce crystal polymorphs.

The compounds represented by Formula (I) of the present invention orpharmaceutically acceptable salts thereof may form prodrugs. The presentinvention also encompasses such various prodrugs. Prodrugs arederivatives of the compounds of the present invention that havechemically or metabolically degradable groups, and compounds that areconverted to the pharmaceutically active compounds of the presentinvention through solvolysis or under physiological conditions in vivo.Prodrugs include compounds that are converted to the compoundsrepresented by Formula (I) through enzymatic oxidation, reduction,hydrolysis or the like under physiological conditions in vivo, compoundsthat are converted to the compounds represented by Formula (I) throughhydrolysis by gastric acid etc., and the like. Methods for selecting andpreparing suitable prodrug derivatives are described in, for example,“Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs themselves mayhave some activity.

When the compounds represented by Formula (I) or pharmaceuticallyacceptable salts thereof have hydroxyl group(s), prodrugs includeacyloxy derivatives and sulfonyloxy derivatives that are prepared by,for example, reacting compounds having hydroxyl group(s) with suitableacyl halide, suitable acid anhydride, suitable sulfonyl chloride,suitable sulfonyl anhydride and mixed anhydride, or with a condensingagent. For example, they include CH₃COO—, C₂H₅COO—, tert-BuCOO—,C₁₅H₃₁COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH₂CH₂COO—, CH₃CH(NH₂)COO—,CH₂N(CH₃)₂COO—, CH₃SO₃—, CH₃CH₂SO₃—, CF₃SO₃—, CH₂FSO₃—, CF₃CH₂SO₃—,p-CH₃O-PhSO₃—, PhSO₃— and p-CH₃PhSO₃.

The compounds of the present invention have an antagonistic activity forthe P2X₇ receptor, and therefore, are useful as a therapeutic and/orpreventive agent for diseases associated with the P2X₇ receptor. As thediseases associated with the P2X₇ receptor, pain, central nervous systemdiseases, immune diseases and inflammatory diseases and the like,preferably pain are exemplified (Non-patent Document 7-8 and PatentDocument 1 etc.).

As pain, pain associated with zoster, postherpetic neuralgia, trigeminalneuralgia, thalamic pain, cancer pain, postoperative pain, menstrualpain, labor pain, chest pain, abdominal pain, colic pain, lumbarbackache, headache, migraine, sciatica, sore muscle, orofacial pain,toothache, glossagra, shoulder pain, nociceptive pain, pain associatedwith deafferentation, psychogenic pain and the like; pain associatedwith the disease such as entrapment neuropathy, carpal canal syndrome,diabetes, Guillain-Barre syndrome, myofascial pain syndrome,fibromyalgia syndrome, complex regional pain syndrome, causalgia,Hansen's disease, spinal cord injury, stroke, multiple sclerosis,Parkinson's disease, endometriosis, hernia of intervertebral disk,arthritis, rheumatoid arthritis, osteoarthritis, cervical spondylosisdeformans, spinal canal stenosis, thoracic outlet syndrome, traumaticbrachial plexus injury syndrome, shoulder-hand syndrome, whiplashinjury, cholelithiasis, pancreatitis, cystitis, urethritis, urinarycalculosis, prostatitis, ulcerative colitis, Crohn's disease, irritablebowel syndrome, bone fracture, osteoporosis, gout, cauda equinasyndrome, ankylosing spondylitis, painful spasm, ABC syndrome, skindisease, arteriosclerosis obliterans, Buerger's disease, Raynaud'sphenomenon, gangrene, temporomandibular arthrosis, somatoform disorder,somatization disorder, depression and the like; pain associated withdrug therapy, and pain associated with radiation therapy areexemplified. Additionally, effects for opioid tolerance can be expected.

Preferably, as pain, pain associated with zoster, postherpeticneuralgia, trigeminal neuralgia, thalamic pain, cancer pain,postoperative pain, sciatica, pain associated with deafferentation andthe like;

pain associated with the disease such as entrapment neuropathy, carpalcanal syndrome, diabetes, Guillain-Barre syndrome, myofascial painsyndrome, fibromyalgia syndrome, complex regional pain syndrome,causalgia, spinal cord injury, stroke, multiple sclerosis, Parkinson'sdisease, hernia of intervertebral disk, arthritis, rheumatoid arthritis,osteoarthritis, cervical spondylosis deformans, spinal canal stenosis,traumatic brachial plexus injury syndrome, shoulder-hand syndrome,cystitis, ulcerative colitis, Crohn's disease, irritable bowel syndrome,gout, depression and the like;pain associated with drug therapy, and pain associated with radiationtherapy are exemplified. Additionally, effects for opioid tolerance canbe expected.

As central nervous system diseases, Alzheimer's disease, Cerebralamyloid angiopathy, Parkinson's disease, Creutzfeldt-Jakob disease,Huntington's chorea, depression, schizophrenia, attention deficithyperactivity disorder, sleep disorder, autism spectrum disorder,epilepsy, stroke, multiple sclerosis, spinal cord injury, amyotrophiclateral sclerosis, opioid dependence, cocaine dependence, nicotinedependence and the like are exemplified.

Preferably, as central nervous system diseases, Alzheimer's disease,Cerebral amyloid angiopathy, Parkinson's disease, depression,schizophrenia, attention deficit hyperactivity disorder, sleep disorder,autism spectrum disorder, epilepsy, stroke, multiple sclerosis, spinalcord injury, amyotrophic lateral sclerosis, opioid dependence, cocainedependence, nicotine dependence and the like are exemplified.

As immune diseases and inflammatory diseases, rheumatoid arthritis,osteoarthritis, asthma, bronchitis, chronic obstructive pulmonarydisease, pulmonary emphysema, septic shock, hepatitis, hepatic fibrosis,hepatic cirrhosis, cholecystitis, glomerulonephritis, nephroticsyndrome, pancreatitis, cystitis, urethritis, prostatitis, ulcerativecolitis, Crohn's disease, irritable bowel syndrome, psoriasis, atopicdermatitis, contact dermatitis, eczematous dermatitis, delayed-typehypersensitivity reaction, conjunctivitis, uveitis, growth andmetastasis of malignant cell (prostate cancer, breast cancer, lungcancer, uterine cancer, pancreatic cancer, colorectal cancer etc.),leukemia, meningitis, burn injury, glossitis, gingivitis, periodontaldisease, esophagitis and the like are exemplified. It is possible thatrejection associated with allograft or blood transfusion is involved inthe P2X₇ receptor. As the other diseases associated with the P2X₇receptor, circulatory diseases such as atherosclerosis, ischemic heartdisease, diabetes and the like, bone diseases such as osteoporosis, bonePaget's disease, osteonecrosis, temporomandibular arthrosis and thelike, and urologic diseases such as overactive bladder, stress urinaryincontinence, prostatomegaly and the like are exemplified.

Preferably, as immune diseases and inflammatory diseases, rheumatoidarthritis, arthritis, osteoarthritis, asthma, bronchitis, chronicobstructive pulmonary disease, cystitis, ulcerative colitis, Crohn'sdisease and the like are exemplified.

(Synthetic Procedures for the Compound of the Present Invention)

For example, the compounds represented by Formula (I) of the presentinvention can be prepared by the general procedures described below. Thestarting materials and reaction reagents used in such synthesis arecommercially available or can be synthesized according to methods wellknown in the art using the compounds commercially available. The methodsfor extraction, purification and the like may be carried out by usingthe usual method for the experiments of organic chemistry.

The compounds of the present invention can be synthesized by referringto the known methods in the art.

In all the following steps, when a substituent which interferes with thereaction, e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy, ispossessed, the substituent is protected by the method such as thosedescribed in Protective Groups in Organic Synthesis, Theodora W Greene(John Wiley & Sons) in advance, and the protective group may be removedat a desirable step.

During all the following steps, the order of the steps to be performedmay be appropriately changed. In each step, an intermediate may beisolated and then used in the next step.

In this description, meanings of each abbreviation are as follows:

-   BINAP: 2,2′-bis(Diphenylphosphino)-1,1′-binaphthyl-   Boc: tert-Butoxycarbonyl-   Cbz: Benzyloxycarbonyl-   DEAD: Diethyl azodicarboxylate-   DIAD: Diisopropyl azodicarboxylate-   DIBAL: Diisobutylaluminum hydride-   DIEA: N,N-Diisopropylethylamine-   DMA: N,N-Dimethylacetamide-   DMAP: 4-Dimethylaminopyridine-   DMF: N,N-Dimethylformamide-   DMSO: Dimethylsulfoxide-   DPPF: 1,1′-bis(Diphenylphosphino)ferrocene-   EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   HATU: O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   Me: Methyl-   NBS: N-Bromosuccinimide-   NCS: N-Chlorosuccinimide-   NIS: N-Iodosuccinimide-   NMP: N-Methylpyrrolidone-   Pd₂(dba)₃ bis(Dibenzylideneacetone)palladium-   Pd(OAc)₂: Palladium acetate-   Pd(PPh₃)₄: Tetrakis(triphenylphosphine)palladium-   Pd₂(dba)₃ tris(Dibenzylideneacetone)bispalladium-   PdCl₂(dppf): [1,1′-bis(Diphenylphosphino)ferrocene]palladium(II)    dichloride-   Ph: Phenyl-   PMB: para-Methoxybenzyl-   TBAF: Tetrabutylammonium fluoride-   TBDPS: tert-Butyldiphenylsilyl-   TBS: tert-Butyldimethylsilyl-   TFA: Trifluoroacetic acid-   t-Bu: tert-Butyl-   Xantphos: 4,5′-bis(Diphenylphosphino)-9,9′-dimethylxanthene-   X-Phos: 2,4,6-Triisopropyl-2′-(dicyclohexylphosphino)biphenyl    [Method A]

wherein

Hal is each independently halogen;

PG is an appropriate protecting group of a hydroxy group;

G¹ is a leaving group such as halogen, substituted or unsubstitutedalkylsulfanyl, substituted or unsubstituted alkylsulfinyl, orsubstituted or unsubstituted alkylsulfonyl;

-L^(A)- is an appropriate group forming Ring Q and represented by-L^(A′)-C(R^(A1))(R^(A2))—, -L^(A′)—(C(R^(A1))(R^(A2)))₂— or the like;

-L^(A′)- is N(R^(A3)), O, S or the like;

R^(A1), R^(A2), and R^(A3) are each independently a hydrogen atom or agroup selected from the substituent group C1;

Z^(2A) is C(R^(5a)) or N; and

the other symbols are the same as the above (1).

Step 1

A compound (A-3) can be synthesized by the reaction of the compound(A-1) with a compound (A-2) in the presence of a base in the appropriatesolvent.

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium carbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.), pyridine, triethylamine, DIEA andthe like are exemplified. 1.0 or more mole equivalent(s), preferably 1.0to 2.0 mole equivalent(s) can be used per an equivalent of the compound(A-2).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethaneetc.), halogenated hydrocarbons (e.g., chloroform, dichloromethaneetc.), DMF, DMSO, NMP, acetonitrile, pyridine and the like areexemplified. The reaction solvent may be used alone or in combination.

The reaction temperature is 0° C. to 80° C., preferably 0° C. to 40° C.

The reaction time is 0.5 hours to 48 hours, preferably 1 hour to 16hours.

The obtained desired compound (A-3) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 2

A compound (A-4) can be synthesized by the reaction of the compound(A-3) with para-methoxybenzyl alcohol in the presence of a base in theappropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of thepara-methoxybenzyl alcohol, preferably 1.0 to 3.0 mole equivalent(s) canbe used per an equivalent of the compound (A-3).

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium carbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.) and the like are exemplified. 1.0or more mole equivalent(s), preferably 1.0 to 2.0 mole equivalent(s) canbe used per an equivalent of the compound (A-3).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), NMP, acetonitrile, DMA and the like are exemplified. The reactionsolvent may be used alone or in combination.

The reaction temperature is 0° C. to 100° C., preferably 0° C. to 80° C.

The reaction time is 0.5 hours to 24 hours, preferably 1 hour to 8hours.

The obtained desired compound (A-4) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 3

A compound (A-6) can be synthesized by the reaction of the compound(A-4) with the compound (A-5) in the presence of a metal catalyst and aligand, or a base or an acid without any solvent or in the appropriatesolvent as necessary.

In this reaction, 1.0 or more mole equivalent(s) of the compound (A-5),preferably 1.0 to 5.0 mole equivalent(s) can be used per an equivalentof the compound (A-4).

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium carbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.), pyridine, triethylamine, DIEA andthe like are exemplified. 1.0 or more mole equivalent(s), preferably 1.0to 5.0 mole equivalent(s) can be used per an equivalent of the compound(A-4).

As the acid, for example, acetic acid, propionic acid and the like areexemplified. 1.0 or more mole equivalent(s), preferably 1.0 to 5.0 moleequivalent(s) can be used per an equivalent of the compound (A-4).

As the metal catalyst, Pd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃)₄,bis(triphenylphosphine)palladium(II) dichloride,bis(tri-tert-butylphosphine) palladium, PdCl₂(dppf) and the like areexemplified. 0.001 to 0.5 mole equivalent(s) can be used per anequivalent of the compound (A-4).

As the ligand, DPPF, BINAP, Xantphos, X-Phos and the like areexemplified. 0.001 to 0.5 mole equivalent(s) can be used per anequivalent of the compound (A-4).

As the reaction solvent, alcohols (e.g., tert-butanol, isopropanoletc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene etc.),saturated hydrocarbons (e.g., cyclohexane, hexane etc.), ethers (e.g.,tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane etc.),halogenated hydrocarbons (e.g., chloroform, dichloromethane etc.), DMF,DMSO, NMP, acetonitrile, pyridine, water and the like are exemplified.The reaction solvent may be used alone or in combination.

The reaction temperature is 0 to 200° C., under microwave irradiation asnecessary, preferably 0 to 150° C.

The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 18 hours.

The obtained desired compound (A-6) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 4

A compound (A-7) can be synthesized by the reaction of the compound(A-6) in the presence of an acid without any solvent or in theappropriate solvent.

As the acid, for example, hydrochloric acid, sulfuric acid, hydrobromicacid, TFA, acetic acid and the like are exemplified. 1.0 or more moleequivalent(s), preferably 1.0 to 5.0 mole equivalent(s) can be used peran equivalent of the compound (A-6).

As the reaction solvent, alcohols (e.g., tert-butanol, isopropanoletc.), aromatic hydrocarbons (e.g., toluene, benzene, xylene etc.),saturated hydrocarbons (e.g., cyclohexane, hexane etc.), ethers (e.g.,tetrahydrofuran, diethylether, dioxane, dimethoxyethane etc.),hydrocarbon halides (e.g., chloroform, dichloromethane etc.),acetonitrile, water and the like are exemplified. The reaction solventmay be used alone or in combination.

The reaction temperature is 0 to 150° C., under microwave irradiation asnecessary, preferably 0 to 100° C.

The reaction time is 0.1 to 24 hours, preferably 0.5 hours to 8 hours.

The obtained desired compound (A-7) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 5

A compound (IA-1) can be synthesized by the reaction of the compound(A-7) in the presence of triphenylphosphine and a condensing agent or inthe presence of a base in the appropriate solvent.

As the condensing agent, DEAD, DIAD, iodine and the like areexemplified. 1.0 or more mole equivalent(s), preferably 1.0 to 5.0 moleequivalent(s) can be used per an equivalent of the compound A-7.

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium bicarbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.), pyridine, triethylamine, DIEA andthe like are exemplified. 2.0 or more mole equivalent(s), preferably 2.0to 5.0 mole equivalent(s) can be used per an equivalent of the compound(A-7).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), hydrocarbon halides (e.g., chloroform, dichloromethane etc.),ethyl acetate, acetonitrile and the like are exemplified. The reactionsolvent may be used alone or in combination.

The reaction temperature is 0° C. to 80° C., preferably 10° C. to 40° C.

The reaction time is 0.1 hours to 12 hours, preferably 0.2 hours to 6hours.

The obtained desired compound (IA-1) can be purified by the methodswhich are usually used (e.g., column chromatography, recrystallizationetc.) and can be optically resolved by preparative SFC (liquid carbondioxide-methanol) using a chiral column, as necessary.

[Method B]

wherein

Hal is each independently halogen;

PG is an appropriate protecting group of a hydroxy group;

-L^(B)- is an appropriate group forming Ring Q and represented by-L^(B′)—C(R^(A1))(R^(A2))— or the like;

-L^(B′)- is N(R^(A3)), O, S or the like;

R^(A1), R^(A2), R^(A3), and Z^(2A) are the same as the method A; and

the other symbols are the same as the above (1).

Step 1

A compound (B-3) can be synthesized by the reaction of the compound(B-1) with the compound (B-2) in the presence of a palladium catalystand a ligand or in the presence of a base without any solvent or in theappropriate solvent as necessary.

In this reaction, 1.0 or more mole equivalent(s) of the compound (B-2),preferably 1.0 to 3.0 mole equivalent(s) can be used per an equivalentof the compound (B-1).

As the palladium catalyst, Pd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃)₄,bis(triphenylphosphine)palladium(II) dichloride,bis(tri-tert-butylphosphine)palladium, PdCl₂(dppf) and the like areexemplified. 0.001 to 0.5 mole equivalent(s) can be used per anequivalent of the compound (B-1).

As the ligand, for example, triphenylphosphine, DPPF, BINAP, Xantphos,X-Phos and the like are exemplified. 0.001 to 0.5 mole equivalent(s) canbe used per an equivalent of the compound (B-1).

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium carbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.), pyridine, triethylamine, DIEA andthe like are exemplified. 1.0 or more mole equivalent(s), preferably 1.0to 5.0 mole equivalent(s) can be used per an equivalent of the compound(B-1).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), hydrocarbon halides (e.g., chloroform, dichloromethane etc.),DMF, DMSO, NMP, acetonitrile, pyridine and the like are exemplified. Thereaction solvent may be used alone or in combination.

The reaction temperature is 0 to 200° C., under microwave irradiation asnecessary, preferably 0 to 150° C.

The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 18 hours.

The obtained desired compound (B-3) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 2

A compound (B-4) can be synthesized by the reaction of the compound(B-3) with a reducing agent in the appropriate solvent.

As the reducing agent, sodium borohydride, lithium borohydride, lithiumaluminum hydride, DIBAL and the like are exemplified. 1.0 or more moleequivalent(s), preferably 1.0 to 10.0 mole equivalent(s) can be used peran equivalent of the compound (B-3).

As the reaction solvent, alcohols (e.g., methanol, ethanol,tert-butanol, isopropanol etc.), aromatic hydrocarbons (e.g., toluene,benzene, xylene etc.), ethers (e.g., tetrahydrofuran, diethylether,dioxane, dimethoxyethane etc.), hydrocarbon halides (e.g., chloroform,dichloromethane etc.), DMF, NMP, acetonitrile, water and the like areexemplified. The reaction solvent may be used alone or in combination.

The reaction temperature is 0 to 150° C., preferably 20 to 150° C.

The reaction time is 0.1 to 48 hours, preferably 1 hour to 24 hours.

The obtained desired compound (B-4) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 3

A compound (B-5) can be synthesized by the reaction of the compound(B-4) according to the synthetic procedures described in the step 4 ofthe method A.

The obtained desired compound (B-5) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 4

A compound (B-6) can be synthesized by the reaction of the compound(B-5) in the presence of triphenylphosphine, imidazole, and iodine inthe appropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of triphenylphosphine,preferably 1.0 to 3.0 mole equivalent(s) can be used per an equivalentof the compound (B-5).

In this reaction, 1.0 or more mole equivalent(s) of imidazole,preferably 1.0 to 5.0 mole equivalent(s) can be used per an equivalentof the compound (B-5).

In this reaction, 1.0 or more mole equivalent(s) of iodine, preferably1.0 to 3.0 mole equivalent(s) can be used per an equivalent of thecompound (B-5).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), hydrocarbon halides (e.g., chloroform, dichloromethane etc.),ethyl acetate, acetonitrile and the like are exemplified. The reactionsolvent may be used alone or in combination.

The reaction temperature is 0° C. to 80° C., preferably 10° C. to 40° C.

The reaction time is 0.1 hours to 12 hours, preferably 0.2 hours to 6hours.

The obtained desired compound (B-6) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 5

A compound (B-8) can be synthesized by the reaction of the compound(B-6) with the compound (B-7) according to the synthetic proceduresdescribed in the step 1 of the method A.

The obtained desired compound (B-8) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 6

A compound (B-9) can be synthesized by the reaction of the compound(B-8) according to the synthetic procedures described in the step 4 ofthe method A.

The obtained desired compound (B-9) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 7

A compound (IB-1) can be synthesized by the reaction of the compound(B-9) according to the synthetic procedures described in the step 5 ofthe method A.

The obtained desired compound (IB-1) can be purified by the methodswhich are usually used (e.g., column chromatography, recrystallizationetc.) and can be optically resolved by preparative SFC (liquid carbondioxide-methanol) using a chiral column, as necessary.

[Method C]

wherein

M is alkaline metal or alkaline earth metal;

Hal is each independently halogen;

-L^(C)- is an appropriate group forming Ring Q and represented by—(C(R^(A1))(R^(A2)))₂—, —(C(R^(A1))(R^(A2)))₃— or the like;

R^(A1), R^(A2), and Z^(2A) are the same as the method A; and

the other symbols are the same as the above (1).

Step 1

A compound (C-3) can be synthesized by the reaction of the compound(C-1) with the compound (C-2) in the presence of a metal catalyst in theappropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of the compound (C-2),preferably 1.0 to 3.0 mole equivalent(s) can be used per an equivalentof the compound (C-1).

As the metal catalyst, for example, trisacetylacetonato iron and thelike are exemplified. 0.001 to 0.5 mole equivalent(s) can be used per anequivalent of the compound (C-1).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), ethers (e.g., tetrahydrofuran, diethylether, dioxane,dimethoxyethane etc.) and the like are exemplified. The reaction solventmay be used alone or in combination.

The reaction temperature is −78 to 100° C., preferably −78 to 40° C.

The reaction time is 0.1 to 8 hours, preferably 0.2 hours to 4 hours.

The obtained desired compound (C-3) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 2

A compound (C-4) can be synthesized by the reaction of the compound(C-3) according to the synthetic procedures described in the step 2 ofthe method A.

The obtained desired compound (C-4) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 3

A compound (C-6) can be synthesized by the reaction of the compound(C-4) with the compound (C-5) according to the synthetic proceduresdescribed in the step 1 of the method B.

The obtained desired compound (C-6) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 4

A compound (C-7) can be synthesized by the reaction of the compound(C-6) according to the synthetic procedures described in the step 4 ofthe method A.

The obtained desired compound (C-7) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 5

A compound (C-9) can be synthesized by the reaction of the compound(C-7) with a nucleophile (C-8) in the appropriate solvent.

As the nucleophile (C-8), organic lithium reagents (alkyl lithium, allyllithium etc.), Grignard reagents (alkylmagnesium bromide, allylmagnesiumbromide etc.), and mixed reagents of these with metal salts areexemplified. 1.0 or more mole equivalent(s), preferably 1.0 to 5.0 moleequivalent(s) can be used per an equivalent of the compound (C-7).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), ethers (e.g., tetrahydrofuran, diethylether, dioxane,dimethoxyethane etc.) and the like are exemplified. The reaction solventmay be used alone or in combination.

The reaction temperature is −78 to the reflux temperature of thesolvent, preferably −40 to 0° C.

The reaction time is 0.5 to 24 hours, preferably 1 hour to 8 hours.

The obtained desired compound (C-9) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

The nucleophile (C-8) can be adjusted by the lithiation of a haliderepresented by (R^(2c)R^(2d)C)—X using an alkyl lithium such asn-butyllithium.

As the reaction solvent, tetrahydrofuran, dioxane and the like areexemplified. The reaction solvent is not specifically limited as long asit is a solvent that does not react with alkyl lithium. The temperatureof the lithiation reaction is preferably about −78° C. to 0° C.

Step 6

A compound (IC-1) can be synthesized by the cyclization of the compound(C-9) according to the synthetic procedures described in the step 5 ofthe method A.

The obtained desired compound (IC-1) can be purified by the methodswhich are usually used (e.g., column chromatography, recrystallizationetc.) and can be optically resolved by preparative SFC (liquid carbondioxide-methanol) using a chiral column, as necessary.

[Method D]

wherein

PG is an appropriate protecting group of a hydroxy group;

RD is substituted or unsubstituted alkyl;

-L^(D)- is an appropriate group forming Ring Q and represented by—(C(R^(A1))(R^(A2)))²—, —(C(R^(A1))(R^(A2)))₃— or the like;

R^(A1) and R^(A2) are the same as the method A; and the other symbolsare the same as the above (1).

Step 1

A compound (D-2) can be synthesized by the reaction of the compound(D-1) with Meldrum's acid in the presence of a condensing agent and abase in the appropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of the Meldrum's acid,preferably 1.0 to 3.0 mole equivalent(s) can be used per an equivalentof the compound (D-1).

As the condensing agent, dicyclohexylcarbodiimide, carbonyldiimidazole,dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC,4-(4,6-dimethoxy-1,3,5,-triazin-2-O-4-methylmorpholinium chloride, HATUand the like are exemplified. 1 to 5 mole equivalent(s) can be used peran equivalent of a compound μl.

As the base, for example, metal carbonate (e.g., sodium carbonate,potassium carbonate, cesium carbonate etc.), pyridine, triethylamine,DIEA and the like are exemplified. 1.0 or more mole equivalent(s),preferably 1.0 to 5.0 mole equivalent(s) can be used per an equivalentof the compound (D-1).

As the reaction solvent, ethers (e.g., tetrahydrofuran, diethylether,dioxane, dimethoxyethane etc.), hydrocarbon halides (e.g., chloroform,dichloromethane etc.), DMA, DMF, DMSO, NMP, acetonitrile and the likeare exemplified. The reaction solvent may be used alone or incombination.

The reaction temperature is −20° C. to 60° C., preferably 0° C. to 30°C.

The reaction time is 0.1 to 24 hours, preferably 1 hour to 12 hours.

The obtained desired compound (D-2) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 2

A compound (D-3) can be synthesized by the reaction of the compound(D-2) with an oxidizing agent in the appropriate solvent.

As the oxidizing agent, for example,1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate), iodobenzene diacetate and the like areexemplified. 1.0 or more mole equivalent(s), preferably 1.0 to 3.0 moleequivalent(s) can be used per an equivalent of the compound (D-2).

As the reaction solvent, alcohols (e.g., methanol, ethanol,tert-butanol, isopropanol etc.), aromatic hydrocarbons (e.g., toluene,benzene, xylene etc.), ethers (e.g., tetrahydrofuran, diethylether,dioxane, dimethoxyethane etc.), acetonitrile and the like areexemplified. The reaction solvent may be used alone or in combination.

The reaction temperature is 0 to 60° C., preferably 0 to 40° C.

The reaction time is 0.1 to 144 hours, preferably 1 hour to 24 hours.

The obtained desired compound (D-3) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 3

A compound (D-5) can be synthesized by the cyclization of the compound(D-3) with the compound (D-4) in the presence of a base in theappropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of the compound (D-4),preferably 1.0 to 2.0 mole equivalent(s) can be used per an equivalentof the compound (D-3).

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium carbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.), pyridine, triethylamine, DIEA andthe like are exemplified. 2.0 or more mole equivalent(s), preferably 2.0to 5.0 mole equivalent(s) can be used per an equivalent of the compound(D-4).

As the reaction solvent, alcohols (e.g., methanol, ethanol,tert-butanol, isopropanol etc.), aromatic hydrocarbons (e.g., toluene,benzene, xylene etc.), ethers (e.g., tetrahydrofuran, diethylether,dioxane, dimethoxyethane etc.), hydrocarbon halides (e.g., chloroform,dichloromethane etc.), acetonitrile and the like are exemplified. Thereaction solvent may be used alone or in combination.

The reaction temperature is 0° C. to the reflux temperature of thesolvent, preferably 20 to 80° C.

The reaction time is 0.1 to 24 hours, preferably 1 hour to 8 hours.

The obtained desired compound (D-5) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 4

A compound (D-6) can be synthesized by the reaction of the compound(D-5) according to the synthetic procedures described in the step 4 ofthe method A.

The obtained desired compound (D-6) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 5

A compound (ID-1) can be synthesized by the cyclization of the compound(D-6) according to the synthetic procedures described in the step 5 ofthe method A.

The obtained desired compound (ID-1) can be purified by the methodswhich are usually used (e.g., column chromatography, recrystallizationetc.) and can be optically resolved by preparative SFC (liquid carbondioxide-methanol) using a chiral column, as necessary.

[Method E]

wherein

Hal is halogen; and

the other symbols are the same as the above (1).

Step 1

A compound (IE-2) can be synthesized by the reaction of the compound(IE-1) with a halide reagent in the appropriate solvent.

As the halide reagent, NCS, NBS, NIS, bromine and the like areexemplified.

In this reaction, 1.0 or more mole equivalent(s) of the halide reagent,preferably 1.0 to 3.0 mole equivalent(s) can be used per an equivalentof the compound (IE-1).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), hydrocarbon halides (e.g., chloroform, dichloromethane etc.),DMF, DMSO, NMP, acetonitrile and the like are exemplified. The reactionsolvent may be used alone or in combination.

The reaction temperature is 0 to 120° C., preferably 0 to 80° C.

The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 18 hours.

The obtained desired compound (IE-2) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

As a reaction following the method E, the Suzuki coupling reaction isexemplified below, but there is no limitation to the Suzuki couplingreaction, and a substituent can be introduced using a known method inthis field.

[Method F]

wherein

R^(A) and R^(B) are each independently hydrogen, or substituted orunsubstituted alkyl, or are taken together to form a substituted orunsubstituted non-aromatic heterocycle;

Hal is halogen; and

the other symbols are the same as the above (1).

A compound (IF-1) can be synthesized by the reaction of the compound(IE-2) obtained in the method E with boronic acid or boronic acid ester(F-1) in the presence of a metal catalyst and a base in the appropriatesolvent.

In this reaction, 1.0 or more mole equivalent(s) of the boronic acid orboronic acid ester (F-1), preferably 1.0 to 5.0 mole equivalent(s) canbe used per an equivalent of the compound (IE-2).

As the metal catalyst, Pd(OAc)₂, Pd₂(dba)₃, Pd(PPh₃)₄,bis(triphenylphosphine)palladium(II) dichloride,bis(tri-tert-butylphosphine)palladium, PdCl₂(dppf) and the like areexemplified. 0.001 to 0.5 mole equivalent(s) can be used per anequivalent of the compound (IE-2).

As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide,potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, cesiumcarbonate, potassium bicarbonate, sodium hydrogen carbonate, sodiumphosphate, sodium hydrogen phosphate, potassium phosphate, potassiumhydrogen phosphate and the like can be exemplified. 1.0 to 10.0 moleequivalent(s) can be used per an equivalent of the compound (IE-2).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethaneetc.), DMF, DMA, NMP, DMSO, water and a mixed solvent thereof and thelike are exemplified.

The reaction temperature is 20 to 250° C., under microwave irradiationas necessary, preferably 0 to 200° C.

The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.

The obtained desired compound (IF-1) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

[Method G]

wherein

-LG- is an appropriate group forming Ring Q and represented by—C(R^(A1))(R^(A2))—, —(C(R^(A1))(R^(A2)))²— or the like;

R^(A1) and R^(A2) are the same as the method A; and the other symbolsare the same as the above (1).

Step 1

A compound (G-3) can be synthesized by the reaction of a compound (G-1)with a compound (G-2) that are obtained according to the syntheticprocedures described in the step 1 of the method B according to thesynthesis method described in International Publication WO 2012/020749A.

The obtained desired compound (G-3) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 2

A compound (G-4) can be synthesized by the reaction of the compound(G-3) with phosphorus oxychloride without any solvent or in theappropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of the phosphorusoxychloride, preferably 1.0 to 10.0 mole equivalent(s) can be used perthe compound (G-3).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), mixed solvents thereof and the like are exemplified.

The reaction temperature is 0 to 100° C., preferably 20 to 80° C.

The reaction time is 0.1 to 24 hours, preferably 0.5 hours to 12 hours.

The obtained desired compound (G-4) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 3

A compound (G-6) can be synthesized by the reaction of the compound(G-4) with a compound (G-5) in the appropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of the compound (G-5),preferably 1.0 to 10.0 mole equivalent(s) can be used per the compound(G-6).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), DMF, DMA, NMP, DMSO water, mixed solvents thereof and the likeare exemplified.

The reaction temperature is 20 to 250° C., under microwave irradiationas necessary, preferably 0 to 200° C.

The reaction time is 0.1 to 48 hours, preferably 0.5 hours to 12 hours.

The obtained desired compound (G-6) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 4

A compound (IG-1) can be synthesized by the reaction of the compound(G-6) in the presence of a base in the appropriate solvent.

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal hydride (e.g.,sodium hydride, lithium hydride etc.), metal carbonate (e.g., sodiumcarbonate, potassium carbonate, cesium carbonate etc.), metal alkoxide(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.),metal alkyl (e.g., butyllithium etc.), pyridine, triethylamine, DIEA andthe like are exemplified. 2.0 or more mole equivalent(s), preferably 2.0to 6.0 mole equivalent(s) can be used per an equivalent of the compound(G-6).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), DMF, DMA, NMP, DMSO, mixed solvents thereof and the like areexemplified.

The reaction temperature is 20 to 250° C., under microwave irradiationas necessary, preferably 0 to 150° C.

The reaction time is 0.1 to 48 hours, preferably 0.5 hours to 12 hours.

The obtained desired compound (IG-1) can be purified by the methodswhich are usually used (e.g., column chromatography, recrystallizationetc.) and can be optically resolved by preparative SFC (liquid carbondioxide-methanol) using a chiral column, as necessary.

[Method H]

wherein

-L^(G)- is an appropriate group forming Ring Q and represented by—C(R^(A1))(R^(A2))—, —(C(R^(A1))(R^(A2)))₂— or the like;

R^(A1) and R^(A2) are the same as the method A; and

the other symbols are the same as the above (1).

Step 1

A compound (H-3) can be synthesized by the reaction of a compound (H-1)obtained according to the synthetic procedures described in the step 1of the method G with a compound (H-2) in the presence of a base and aphosphonitrilic chloride trimer.

The obtained desired compound (H-3) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

Step 2

A compound (IH-1) can be synthesized by the reaction of the compound(H-3) with trimethylamine hydrochloride and methanesulfonyl chloride inthe presence of a base in the appropriate solvent.

As the base, for example, metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, tripotassium phosphate etc.), metal carbonate(e.g., sodium carbonate, potassium carbonate, cesium carbonate etc.),metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassiumtert-butoxide etc.), metal alkyl (e.g., butyllithium etc.), pyridine,triethylamine, DIEA and the like are exemplified. 2.0 or more moleequivalent(s), preferably 2.0 to 6.0 mole equivalent(s) can be used peran equivalent of the compound (H-3).

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethylether, dioxane, dimethoxyethaneetc.), DMF, DMA, NMP, DMSO, mixed solvents thereof and the like areexemplified.

The reaction temperature is −10 to 50° C., preferably 0 to 20° C.

The reaction time is 0.1 to 24 hours, preferably 0.5 hours to 12 hours.

The obtained desired compound (IH-1) can be purified by the methodswhich are usually used (e.g., column chromatography, recrystallizationetc.) and can be optically resolved by preparative SFC (liquid carbondioxide-methanol) using a chiral column, as necessary.

In the synthesis of the compound of the present invention, C═O can beappropriately converted to C═S at a desirable step on the basis of thesynthesis method of method α shown below.

[Method α]

wherein each symbol is the same as the above (1).

A compound (Iα′) can be synthesized by the reaction of the compound (Iα)with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphethane-2,4-disulfidein the appropriate solvent.

As the reaction solvent, aromatic hydrocarbons (e.g., toluene, benzene,xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexane etc.),ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, dimethoxyethaneetc.), acetonitrile and the like are exemplified. The reaction solventcan be used alone or in combination.

The reaction temperature is −10 to 110° C., preferably 0 to 80° C.

The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 18 hours.

The obtained desired compound (Iα′) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

In the synthesis of the compound of the present invention, C═S can beappropriately converted to C═N(R⁶) at a desirable step on the basis ofthe synthesis method of method ß shown below. [Method ß]

wherein Y^(1A) is N(R⁶); and the other symbols are the same as the above(1).

A compound (Iα″) can be synthesized by the reaction of the compound(Iα′) obtained by the method α with a compound (Ab-1) in the presence ofan acid or a base in the appropriate solvent.

In this reaction, 1.0 or more mole equivalent(s) of the compound (Ab-1),preferably 1.0 to 5.0 mole equivalent(s) can be used per an equivalentof the compound (Iα′).

As the acid, for example, acetic acid, trifluoroacetic acid,p-toluenesulfonic acid and the like are exemplified. 0.05 or more moleequivalents, preferably 0.1 to 2.0 mole equivalents can be used per anequivalent of the compound (Iα′).

As the base, for example, pyridine, triethylamine, DIEA and the like areexemplified. 1.0 or more mole equivalent(s), preferably 1.0 to 20.0 moleequivalent(s) can be used per an equivalent of the compound (Iα′).

As the reaction solvent, alcohols (e.g., methanol, ethanol,tert-butanol, isopropanol etc.), aromatic hydrocarbons (e.g., toluene,benzene, xylene etc.), saturated hydrocarbons (e.g., cyclohexane, hexaneetc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane,dimethoxyethane etc.), DMF, NMP, acetonitrile, DMA and the like areexemplified. The reaction solvent can be used alone or in combination.

The reaction temperature is 0 to 150° C., preferably 0 to 80° C.

The reaction time is 0.1 to 72 hours, preferably 0.5 hours to 18 hours.

The obtained desired compound (Iα″) can be purified as necessary by themethods which are usually used (e.g., column chromatography,recrystallization etc.).

An optically active form of the compound represented by Formula (I) canbe produced by using an optically active starting material, synthesizingan optically active intermediate by asymmetric synthesis at anappropriate step, or optically resolving racemic intermediates or finalproducts at an appropriate step. The approach for the optical resolutionincludes a method of resolving optical isomers using an optically activecolumn, kinetic optical resolution using enzymatic reaction or the like,crystallization and resolution of diastereomers by salt formation usinga chiral acid or a chiral base, preferential crystallization and thelike.

The preferred compound of the present invention not only has anantagonistic activity for the P2X₇ receptor but also is useful as amedicine and has any or all of the following superior characteristics:

a) The inhibitory activity for CYP enzymes (e.g., CYP1A2, CYP2C9,CYP2C19, CYP2D6, CYP3A4 and the like) is weak.

b) The compound demonstrates good pharmacokinetics, such as a highbioavailability, moderate clearance and the like.

c) The compound has a high metabolic stability.

d) The compound has no irreversible inhibitory effect against CYPenzymes (e.g., CYP3A4) when the concentration is within the rangedescribed in the present description as the measurement conditions.

e) The compound has no mutagenicity.

f) The compound is associated with a low cardiovascular risk.

g) The compound has a high solubility.

h) The compound has a high selectivity for the P2X₇ receptor (e.g., highselectivity in the other receptors of the P2X family).

i) The compound has a high brain distribution.

A pharmaceutical composition of the present invention can beadministered orally or parenterally. Methods for parenteraladministration include dermal, subcutaneous, intravenous, intraarterial,intramuscular, intraperitoneal, transmucosal, inhalation, transnasal,ophthalmic, inner ear or vaginal administration and the like.

In case of oral administration, any forms, which are usually used, suchas oral solid formulations (e.g., tablets, powders, granules, capsules,pills, films or the like), oral liquid formulations (e.g., suspension,emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract,decoction, tincture or the like) and the like may prepared according tothe usual method and administered. The tablets can be sugar-coatedtablets, film-coated tablets, enteric-coating tablets, sustained-releasetablets, troche tablets, sublingual tablets, buccal tablets, chewabletablets or orally dispersing tablets. Powders and granules can be drysyrups. Capsules can be soft capsules, micro capsules orsustained-release capsules.

In case of parenteral administration, any forms, which are usually used,such as injections, drips, external preparations (e.g., ophthalmicdrops, nasal drops, ear drops, aerosols, inhalations, lotion, infusion,liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch,cataplasm, external powder, suppository or the like) and the like can bepreferably administered. Injections can be emulsions whose type is O/W,W/O, O/W/O, W/O/W or the like.

The pharmaceutical composition may be manufactured by mixing aneffective amount of the compound of the present invention with variouspharmaceutical additives suitable for the formulation, such asexcipients, binders, moistening agents, disintegrants, lubricants,diluents and the like. Furthermore, the pharmaceutical composition canbe for pediatric patients, geriatric patients, serious cases oroperations by appropriately changing the effective amount of thecompound of the present invention, formulation and/or variouspharmaceutical additives. The pediatric pharmaceutical compositions arepreferably administered to patients under 12 or 15 years old. Inaddition, the pediatric pharmaceutical compositions can be administeredto patients who are under 27 days old after the birth, 28 days to 23months old after the birth, 2 to 11 years old, 12 to 16 years old, or 18years old. The geriatric pharmaceutical compositions are preferablyadministered to patients who are 65 years old or over.

Although the dosage of a pharmaceutical composition of the presentinvention should be determined in consideration of the patient's age andbody weight, the type and degree of diseases, the administration routeand the like, a usual oral dosage is 0.05 to 300 and preferably 0.1 to100 mg/man/day. For parenteral administration, although the dosagehighly varies with administration routes, a usual dosage is 0.005 to 10and preferably 0.01 to 1 mg/man/day. The dosage may be administered inone to several divisions per day.

The present invention will be described in more detail with referenceto, but not limited to, the following Examples, Reference Examples andTest Examples.

NMR analysis of each example was performed by 400 MHz using DMSO-d₆ orCDCl₃.

“RT” in tables means retention time in LC/MS: liquid columnchromatography/mass analysis and these are measured under the conditionsas below:

-   Condition[1]-   Column: Shim-pack XR-ODS (2.2 μm, i.d.50×3.0 mm) (Shimadzu)-   Flow rate: 1.6 mL/min-   UV detection wavelength: 254 nm-   Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1%    formic acid in acetonitrile solvent.-   Gradient: linear gradient of 10% to 100% solvent [B] for 3 minutes    was performed, and 100% solvent FBI was maintained for 0.5 minute.-   Condition[2]-   Column: ACQUITY UPLC (registered trademark) BEH C18(1.7 μm-   i.d.2.1×50 mm)(Waters)-   Flow rate: 0.8 mL/min-   UV detection wavelength: 254 nm-   Mobile phases: [A] is 10 mmol/L Ammonium Carbonate solution, and FBI    is acetonitrile.-   Gradient: linear gradient of 5% to 100% solvent FBI for 3.5 minutes    was performed, and 100% solvent FBI was maintained for 0.5 minute.-   Condition[3]-   Column: ACQUITY UPLC (registered trademark) BEH C18(1.7 μm-   i.d.2.1×50 mm)(Waters)-   Flow rate: 0.8 mL/min-   UV detection wavelength: 254 nm-   Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1%    formic acid in acetonitrile solvent.-   Gradient: linear gradient of 5% to 100% solvent FBI for 3.5 minutes    was performed, and 100% solvent FBI was maintained for 0.5 minute.-   Condition[4]-   Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d.    2.1×50 mm) (Waters)-   Flow rate: 0.55 mL/minute-   UV detection wavelength: 254 nm-   Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1%    formic acid in acetonitrile solvent.-   Gradient: linear gradient of 5% to 100% solvent [B] for 3 minutes    was performed, and 100% solvent FBI was maintained for 0.5 minute.

The optical resolution was performed under the following Preparativeconditions using a semi-preparative SFC system, available from JASCOCorporation.

-   Preparative condition 1

Column: Two columns, CHIRALPAK ID/SFC (5 μm i.d. 250×20 mm) (DAICEL),were used in series.

-   Flow rate: 30 mL/min-   UV detection wavelength: 220 nm-   Back pressure: 8 MPa-   Mobile phases: [A] is liquid carbon dioxide, and FBI is isopropanol.    35% solvent FBI was maintained, and the solution was sent for 40    minutes.-   Preparative condition 2-   Column: Two columns, CHIRALPAK IC/SFC (5 μm i.d. 250×20 mm)    (DAICEL), were used in series.-   Flow rate: 40 mL/min-   UV detection wavelength: 220 nm-   Back pressure: 8 MPa-   Mobile phases: [A] is liquid carbon dioxide, and [B] is methanol.    30% solvent FBI was maintained, and the solution was sent for 40    minutes.-   Preparative condition 3-   Column: Two columns, CHIRALPAK IC/SFC (5 μm i.d. 250×20 mm)    (DAICEL), were used in series.-   Flow rate: 40 mL/min-   UV detection wavelength: 220 nm-   Back pressure: 10 MPa-   Mobile phases: [A] is liquid carbon dioxide, and [B] is methanol.    25% solvent FBI was maintained, and the solution was sent for 35    minutes.-   Preparative condition 4-   Column: CHIRALPAK IC/SFC (5 μm i.d. 250×20 mm) (DAICEL) was used.    Flow rate: 40 mL/min-   UV detection wavelength: 220 nm-   Back pressure: 15 MPa-   Mobile phases: [A] is liquid carbon dioxide, and [B] is methanol.    25% solvent FBI was maintained, and the solution was sent for 15    minutes.

Example 1 Synthesis of Compound I-0002

Step 1

Under nitrogen atmosphere, 2-(tert-butoxy)-2-phenylethanol (1.43 g, 7.36mmol) was added to a suspension of sodium hydride (60 wt %, 324 mg, 8.10mmol) in tetrahydrofuran (10 mL) and DMF (5 mL) at 0° C. The mixture wasstirred at room temperature for 35 minutes.2-amino-4,6-dichloropyrimidine (1.33 g, 8.10 mmol) was added thereto,and the mixture was stirred at 100° C. for 30 minutes. Water was addedto the reaction mixture. The mixture was extracted with ethyl acetate.The organic layer was washed by water and brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 2 (1150 mg, yield49%).

¹H-NMR (CDCl₃) δ: 1.15 (s, 9H), 4.20-4.31 (m, 2H), 4.84 (dd, J=8.2, 4.0Hz, 1H), 5.02 (brs, 2H), 7.25-7.29 (m, 2H), 7.34 (t, J=7.3 Hz, 2H), 7.41(d, J=7.7 Hz, 2H).

Step 2

Under nitrogen atmosphere, 4-methoxybenzyl alcohol (623 mg, 4.51 mmol)was added to a suspension of sodium hydride (60 wt %, 159 mg, 3.97 mmol)in tetrahydrofuran (7 mL) at 0° C. The mixture was stirred at roomtemperature for 30 minutes. A tetrahydrofuran (7 mL) solution ofCompound 2 (580 mg, 1.80 mmol) was added thereto. The mixture wasstirred at 70° C. for 1 hour. Water was added to the reaction mixture.The mixture was extracted with ethyl acetate. The organic layer waswashed by water and brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica-gel column chromatography (hexane-ethyl acetate) togive Compound 3 (304 mg, yield 40%).

1H-NMR (CDCl₃) δ: 1.14 (s, 9H), 3.81 (s, 3H), 4.11-4.18 (m, 1H), 4.26(dd, J=10.8, 3.8 Hz, 1H), 4.79 (brs, 2H), 4.84 (dd, J=7.8, 4.0 Hz, 1H),5.20 (s, 2H), 5.51 (s, 1H), 6.89 (d, J=7.5 Hz, 2H), 7.23-7.42 (m, 7H).

Step 3

Under nitrogen atmosphere, Compound 3 (135 mg, 0.319 mmol) was dissolvedin toluene (1.5 mL), and 1-bromo-3-chloro-2-methyl benzene (65.5 mg,0.319 mmol), sodium-tert-butoxide (61.3 mg, 0.638 mmol), BINAP (39.7 mg,0.064 mmol), and Pd₂(dba)₃ (29.2 mg, 0.032 mmol) were added thereto. Themixture was stirred at 100° C. for 40 minutes under microwaveirradiation. Water was added to the reaction mixture. The mixture wasextracted with ethyl acetate. The organic layer was washed by water andbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to give Compound4 (165 mg, yield 94%).

1H-NMR (CDCl₃) δ: 1.11 (s, 9H), 2.38 (s, 3H), 3.81 (s, 3H), 4.15 (t,J=9.7 Hz, 1H), 4.31 (dd, J=11.0, 3.5 Hz, 1H), 4.80 (dd, J=8.3, 3.8 Hz,1H), 5.23 (s, 2H), 5.61 (s, 1H), 6.63 (s, 1H), 6.89 (d, J=7.5 Hz, 2H),7.10-7.19 (m, 2H), 7.24-7.32 (m, 7H), 7.82 (d, J=7.8 Hz, 1H).

Step 4

A 4 mol/L hydrochloric acid solution (dioxane solution, 5 mL, 20 mmol)was added to Compound 4 (165 mg, 0.301 mmol). The mixture was stirred atroom temperature for 2 hours. Water was added to the reaction mixture.The mixture was neutralized with the aqueous solution of sodiumhydroxide and extracted with a dichloromethane-methanol mixed solvent.The organic layer was washed by brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to giveCompound 5 (102 mg, yield 91%).

[M+H]=372: Condition [2]: Retention time=1.76 (minutes)

Step 5

DIAD (0.282 mL, 1.45 mmol) was added to a suspension of Compound 5 (60mg, 0.161 mmol) and triphenylphosphine (423 mg, 1.61 mmol) indichloromethane (4 mL). The mixture was stirred at room temperature for30 minutes. Water was added to the reaction mixture. The mixture wasextracted with ethyl acetate. The organic layer was washed by brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 1-0002 (20 mg,yield 35%).

1H-NMR (DMSO-d6) δ: 1.56 (s, 3H), 4.58 (d, J=8.7 Hz, 1H), 4.93 (s, 1H),5.06 (t, J=8.4 Hz, 1H), 5.66 (br, 1H), 6.53 (br, 1H), 6.96-7.04 (m, 2H),7.30-7.44 (m, 5H), 9.58 (brs, 1H).

Example 2 Synthesis of Compound I-0003

Step 1

Under nitrogen atmosphere, 3-chloro-2-methylaniline (105 mg, 0.740 mmol)was added to a suspension of Compound 6 (50 mg, 0.247 mmol) in dioxane(1 mL). The mixture was refluxed by heating for 22 hours. The aqueoussolution of saturated ammonium chloride was added to the reactionmixture. The mixture was extracted with chloroform. The organic layerwas dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica-gelcolumn chromatography (hexane-ethyl acetate) to give Compound 7 (27 mg,yield 36%).

1H-NMR (CDCl₃) δ: 2.38 (s, 3H), 3.91 (s, 3H), 3.98 (s, 3H), 6.89 (s,1H), 7.03 (s, 1H), 7.12-7.19 (m, 2H), 7.84 (d, J=7.8 Hz, 1H).

Step 2

Under nitrogen atmosphere, a 1.03 mol/L DIBAL solution (13.9 mL, 14.3mmol) was added to a tetrahydrofuran (10 mL) solution of Compound 7 (1.0g, 3.25 mmol). The mixture was stirred at 0° C. for 3 hours. Methanoland a saturated Rochelle salt solution were added to the reactionmixture. The mixture was stirred at room temperature for 1 hour. Themixture was extracted with ethyl acetate. The organic layer was washedby water, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to give Compound8 (830 mg, yield 91%).

1H-NMR (CDCl₃) δ: 2.39 (s, 3H), 3.16 (br, 1H), 3.91 (s, 3H), 4.55 (s,2H), 6.14 (s, 1H), 6.77 (br, 1H), 7.12-7.18 (m, 2H), 7.84 (d, J=7.8 Hz,1H).

Step 3

Concentrated hydrochloric acid (20 mL) was added to Compound 8 (650 mg,2.32 mmol). The mixture was stirred at 100° C. for 1.5 hours. Thereaction mixture was neutralized with saturated sodium bicarbonate waterto be a pH of 5. The mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give Compound 9 (535 mg, yield87%). [M+H]=266: Condition [2]: Retention time=1.15 (minutes)

Step 4

Compound 9 (485 mg, 1.83 mmol) was dissolved in dichloromethane (15 mL).Under ice cooling, imidazole (373 mg, 5.48 mmol), triphenylphosphine(622 mg, 2.37 mmol), and iodine (602 mg, 2.37 mmol) were added thereto.The mixture was stirred at room temperature for 30 minutes. The aqueoussolution of saturated ammonium chloride was added to the reactionmixture. The mixture was extracted with ethyl acetate. The organic layerwas washed by water, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waswashed by toluene to give Compound 10 (380 mg, yield 55%).

1H-NMR (DMSO-d6) δ: 2.28 (s, 3H), 4.11 (s, 2H), 5.91 (s, 1H), 7.18-7.27(m, 2H), 7.68 (d, J=6.5 Hz, 1H).

Step 5

Under nitrogen atmosphere, 2-(tert-butoxy)-2-phenylethanol (786 mg, 4.05mmol) was added to a suspension of sodium hydride (60 wt %, 158 mg, 3.95mmol) in DMF (3 mL) at 0° C. Subsequently, a DMF (3 mL) solution ofCompound 10 (380 mg, 1.01 mmol) was added thereto. The mixture wasstirred at 0° C. for 10 minutes. The aqueous solution of saturatedammonium chloride was added to the reaction mixture. The mixture wasextracted with ethyl acetate. The organic layer was washed by water, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 11 (280 mg, yield63%). [M+H]=442: Condition [2]: Retention time=2.40 (minutes)

Step 6

A 4 mol/L hydrochloric acid solution (dioxane solution, 3 mL, 12 mmol)was added to Compound 11 (270 mg, 0.611 mmol). The mixture was stirredat room temperature for 30 minutes. Saturated sodium bicarbonate waterand the aqueous solution of saturated ammonium chloride were added tothe reaction mixture. The mixture was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to give Compound12 (180 mg, yield 76%).

[M+H]=386: Condition [2]: Retention time=1.73 (minutes)

Step 7

Under nitrogen atmosphere, imidazole (48.2 mg, 0.708 mmol) andtriphenylphosphine (74.2 mg, 0.283 mmol) were added to a suspension ofCompound 12 (91 mg, 0.236 mmol) in dichloromethane (2 mL). Iodine (71.8mg, 0.283 mmol) was added thereto at 0° C. The mixture was stirred atroom temperature for 2 hours. The aqueous solution of saturated ammoniumchloride was added to the reaction mixture. The mixture was extractedwith ethyl acetate. The organic layer was washed by water and brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give the crude product ofCompound 13.

Step 8

Under nitrogen atmosphere, the crude product of Compound 13 obtained inthe step 7 was dissolved in DMF (5 mL). Potassium carbonate (81 mg, 0.59mmol) was added thereto. The mixture was stirred at 60° C. for 30minutes. Water was added to the reaction mixture. The mixture wasadjusted to pH 6 with a 10% aqueous solution of citric acid. The mixturewas extracted with ethyl acetate. The organic layer was washed by waterand brine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (hexane-ethyl acetate). An opticallyactive form was separated by preparative SFC (Preparative condition 4)to give Compound I-0003.

¹H-NMR (DMSO-d₆) δ: 1.45 (s, 3H), 4.04 (d, J=12.0 Hz, 1H), 4.23 (d,J=10.2 Hz, 1H), 4.61 (d, J=16.2 Hz, 1H), 4.75 (d, J=16.2 Hz, 1H), 5.33(s, 1H), 5.47 (s, 1H), 6.47 (br, 1H), 6.95-7.03 (m, 2H), 7.23-7.29 (m,3H), 7.34-7.38 (m, 2H), 9.74 (br, 1H).

Reference Example 1 Synthesis of Compound 15

tert-Butyl(3-iodine-phenylpropoxy)dimethylsilane (3.24 g, 8.61 mmol)(the synthesis method is described in Journal of the American ChemicalSociety, 135(14), 5242-5245; 2013) was dissolved in toluene (30 mL).Triphenylphosphine (2.71 g, 10.33 mmol) was added thereto. The mixturewas stirred for 10 hours under reflux by heating. After cooling, theprecipitated solids were filtered, washed by diisopropyl ether, anddried under reduced pressure to give Compound 15 (6.32 g, quant.).

Condition [1] Retention time=2.11 (minutes); [M+H]=511.3

Example 3 Synthesis of Compound I-0005

Step 1

Under nitrogen atmosphere,2-chloro-6-methoxy-4-methylpyrimidinecarboxylate (6.9 g, 34.1 mmol) and3-chloro-2-methylaniline (16.28 mL, 136 mmol) were mixed. The mixturewas stirred for 10 hours under reflux by heating. After cooling, theaqueous solution of saturated ammonium chloride was added thereto. Theaqueous layer was extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 17 (6.9 g, yield66%). Condition [3]: Retention time=4.25 (minutes): [M+H]=308.3

Step 2

Under nitrogen atmosphere, Compound 17 (3 g, 9.75 mmol) was dissolved intetrahydrofuran (30 mL). Under ice cooling, DIBAL (31.2 mL, 32.2 mmol)was added thereto. The mixture was stirred for 1 hour. Methanol and aRochelle salt solution were added thereto. The mixture was stirred atroom temperature. The mixture was extracted with ethyl acetate. Theorganic layer was washed by water, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica-gel column chromatography (hexane-ethylacetate) to give Compound 18 (2.0 g, yield 73%).

Condition [3]: Retention time=2.53 (minutes): [M+H]=280.4

Step 3

Under nitrogen atmosphere, Compound 18 (600 mg, 2.14 mmol) was dissolvedin dichloromethane. Under water cooling, Dess-Martin periodinane (1319mg, 3.11 mmol) was added thereto. The mixture was stirred for 2.5 hours.A 10% aqueous solution of sodium thiosulfate was added thereto. Themixture was stirred for 30 minutes. The reaction mixture was extractedwith ethyl acetate. The organic layer was washed by brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 19 (264.6 mg,yield 44%).

Condition [1]: Retention time=2.17 (minutes): [M+H]=278.0

Step 4

Under nitrogen atmosphere, Compound 15 (747 mg, 1.17 mmol) was dissolvedin tetrahydrofuran (1 mL), and cooled to −78° C. A 1.67 mol/Ln-butyllithium-hexane solution (0.701 mL, 1.17 mmol) was added dropwisethereto. The mixture was stirred at −78° C. for 30 minutes. Atetrahydrofuran (1 mL) solution of the compound 19 (50 mg, 0.18 mmol)was added dropwise thereto. The mixture was stirred at −78° C. for 1hour. The aqueous solution of saturated ammonium chloride was addedthereto. The mixture was heated to room temperature. The aqueous layerwas extracted with dichloromethane. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 20 (89.2 mg,yield 97%).

Condition [1] Retention time=3.51 (minutes): [M+H]=510.3

Step 5

Compound 20 (105 mg, 0.206 mmol) was dissolved in methanol (2 mL).Palladium/carbon (palladium 10%) (about 55% water-moist products) (20mg) was added thereto. The mixture was stirred for 19 hours underhydrogen atmosphere. The reaction mixture was filtered through Celite.The filtrate was concentrated to give the crude product of Compound 21(112 mg).

Condition [1]: Retention time=3.53 (minutes): [M+H]=512.2

Step 6

Sodium iodide (97 mg, 0.644 mmol) was suspended in acetonitrile (2 mL).Chlorotrimethylsilane (70 mg, 0.644 mmol) was added thereto. The mixturewas stirred for 0.5 hours to prepare an iodotrimethylsilane solution.The crude product of Compound 21 (110 mg) obtained in the step 5 wasdissolved in acetonitrile (3 mL). The prepared iodotrimethylsilanesolution was added thereto. The mixture was stirred for 18 hours underreflux by heating. After cooling, the saturated aqueous solution ofsodium hydrogen carbonate and a 10% aqueous solution of sodiumthiosulfate were added thereto. The mixture was stirred. The aqueouslayer was extracted with chloroform. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 22 (14.6 mg,yield 19%).

Condition [1]: Retention time=2.22 (minutes): [M+H]=366.0

Step 7

Compound 22 was dissolved in a 25% hydrogen bromide solution (aceticacid solution) (0.5 mL). The mixture was stirred at room temperature for0.5 hours. The saturated aqueous solution of sodium hydrogen carbonatewas added thereto. The aqueous layer was extracted with dichloromethane.The solvent was evaporated under reduced pressure to give the crudeproduct of Compound 23 (14.2 mg).

Condition [1]: Retention time=2.27 (minutes): [M+H]=446.0

Step 8

The crude product of Compound 23 (14.2 mg) obtained in the step 7 andpotassium carbonate (13.18 mg, 0.095 mmol) were dissolved in DMF (1 mL).The mixture was stirred at 70° C. for 0.5 hours. After cooling, themixture was diluted with water, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby preparative thin-layer chromatography (hexane-ethyl acetate) to giveCompound 1-0005 (5.2 mg, yield 45%).

¹H-NMR (CDCl₃) δ: 1.53 (s, 3H), 1.65-1.78 (m, 2H), 2.17-2.34 (m, 2H),2.69-2.84 (m, 2H), 5.34 (s, 1H), 6.00 (dd, J=5.0, 2.3 Hz, 1H), 6.49 (dd,J=6.9, 2.6 Hz, 1H), 6.97-7.03 (m, 2H), 7.15 (d, J=7.3 Hz, 2H), 7.28 (d,J=7.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 3H).

Example 4 Synthesis of Compound I-0006

Step 1

Under nitrogen atmosphere, Compound 24 (2 g, 10.19 mmol) (the synthesismethod is described in Zhurnal Obshchei Khimii (1963), 5(4), 1446-51)was dissolved in tetrahydrofuran (20 mL). Under ice cooling, sodiumhydride (0.448 g, 11.21 mmol) was added thereto. The mixture was stirredfor 0.5 hours. 4,6-dichloropyrimidin-2-amine (1.671 g, 10.19 mmol) wasadded thereto. The mixture was heated to room temperature, and stirredat room temperature for 3 hours and then stirred at 60° C. for 4 hours.After cooling, the aqueous solution of saturated ammonium chloride wasadded thereto. The mixture was extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to give Compound25 (2.58 g, yield 78%).

Condition [1]: Retention time=2.03 (minutes): [M+H]=324.0

Step 2

Under nitrogen atmosphere, Compound 25 (2.52 g, 7.78 mmol) was dissolvedin tetrahydrofuran (20 mL). Under ice cooling, sodium hydride (0.623 g,15.57 mmol) was added thereto. The mixture was heated to roomtemperature, and stirred for 0.5 hours. Under ice cooling,para-methoxybenzyl alcohol (2.151 g, 15.57 mmol) was added thereto, andthe mixture was heated to 80° C. The mixture was stirred for 2 hours,cooled to room temperature, and diluted with water. The aqueous layerwas extracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate. The residue was purified by silica-gelcolumn chromatography (hexane-ethyl acetate) to give Compound 26 (3.12g, yield 68%).

Condition [1]: Retention time=2.24 (minutes): [M+H]=426.2

Step 3

Under nitrogen atmosphere, Compound 26 (1.5 g, 3.53 mmol),1-bromo-3-chloro-2-methyl benzene (1.087 g, 5.29 mmol), Pd₂(dba)₃ (0.646g, 0.705 mmol), BINAP (0.878 g, 1.41 mmol), and sodium tert-butoxide(0.678 g, 7.05 mmol) were suspended in toluene (15 mL). The mixture wasstirred at 100° C. for 2 hours. After cooling, the mixture wasneutralized with a 5% aqueous solution of citric acid. The aqueous layerwas extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 27 (1.6 g, yield64%).

Condition [1]: Retention time=3.07 (minutes): [M+H]=550.2

Step 4

Compound 27 (1.08 g, 1.531 mmol) was dissolved in a 4 mol/L hydrochloricacid-dioxane solution. The mixture was stirred for 3 hours. Thesaturated aqueous solution of sodium hydrogen carbonate was addedthereto for neutralization. The aqueous layer was extracted withchloroform. The mixture was dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give the crude productof Compound 28 (1.13 g, yield 96%).

Condition [1]: Retention time=1.74 (minutes): [M+H]=386.1

Step 5

The crude product of Compound 28 (1 g) obtained in the step 4 andtriphenylphosphine (1.36 g, 5.18 mmol) were dissolved in tetrahydrofuran(200 mL). Under ice cooling, a 1.9 mol/L DIAD-toluene solution (2.73 mL,5.18 mmol) was added thereto. The mixture was heated to roomtemperature, and stirred for 5 minutes. The mixture was diluted withwater. The aqueous layer was extracted with chloroform. The mixture wasdried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by preparative thin-layerchromatography (hexane-ethyl acetate) to give Compound I-0006 (5.2 mg,yield 1%).

¹H-NMR (CDCl₃) δ: 1.60 (s, 3H), 2.24 (dd, J=14.3, 2.8 Hz, 1H), 2.62-2.71(m, 1H), 3.72-3.79 (m, 1H), 4.16 (dt, J=16.6, 6.1 Hz, 1H), 4.32-4.36 (m,1H), 4.99 (d, J=2.0 Hz, 1H), 6.00 (d, J=3.3 Hz, 1H), 6.53 (dd, J=7.0,2.3 Hz, 1H), 6.98-7.04 (m, 2H), 7.22 (d, J=6.3 Hz, 2H), 7.33 (t, J=7.5Hz, 1H), 7.41 (t, J=7.0 Hz, 2H).

Example 5 Synthesis of Compound I-0007

Step 1

Under nitrogen atmosphere, magnesium (1.59 g, 65.4 mmol) was suspendedin tetrahydrofuran (30 mL). 2-(2-bromo ethyl)-1,3-dioxane (1 mL, 7.39mmol) and iodine (8.8 mg, 0.035 mmol) were added thereto. The mixturewas stirred. Under water cooling, 2-(2-bromo ethyl)-1,3-dioxane (7.12mL, 52.6 mmol) was slowly added dropwise thereto. The mixture wasstirred at room temperature for 3.5 hours to prepare a Grignard reagent.2,4,6-Trichloropyrimidine was dissolved in tetrahydrofuran (40 mL), andcooled to −78° C. The prepared Grignard reagent was added dropwisethereto. A tetrahydrofuran (10 mL) solution of trisacetylacetonatoiron(0.963 g, 2.73 mmol) was added dropwise thereto. The mixture was stirredat −78° C. for 20 minutes. The aqueous solution of ammonium chloride wasadded thereto. The mixture was heated to room temperature. The aqueouslayer was extracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 30 (5.37 g, yield37%).

Condition [1]: Retention time=1.76 (minutes): [M+H]=263.1

Step 2

Under nitrogen atmosphere, para-methoxybenzyl alcohol (62.3 g, 451 mmol)and Compound 30 (113 g, 429 mmol) were dissolved in tetrahydrofuran(1130 mL). Under ice cooling, sodium hydride (18.89 g, 472 mmol) wasadded thereto under stirring. After stirring for 2.5 hours, sodiumhydride (2 g, 50 mmol) was added thereto. The mixture was stirred for 2hours. The mixture was diluted with water, and heated to roomtemperature. The aqueous layer was extracted with ethyl acetate. Theorganic layer was washed by water and brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained solid was washed by a mixed solution of ethyl acetate andhexane, and dried under reduced pressure to give Compound 31 (61.1 g,yield 39%).

Condition [1]: Retention time=2.27 (minutes): [M+H]=365.2

Step 3

Under nitrogen atmosphere, Compound 31 (1 g, 2.74 mmol), 3-chloro-2methylaniline (776 mg, 5.48 mmol), palladium acetate (61.5 mg, 0.274mmol), Xantphos (238 mg, 0.411 mmol), and cesium carbonate (2679 mg,8.22 mmol) were suspended in 1,4-dioxane (10 mL). The mixture wasstirred at 110° C. for 1 hour. After cooling, the mixture was dilutedwith water, and extracted with ethyl acetate. The organic layer waswashed by brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica-gel column chromatography (hexane-ethyl acetate) to give

Compound 32 (715.5 mg, yield 56%).

Condition [1]: Retention time=2.33 (minutes): [M+H]=470.2

Step 4

Compound 32 (682 mg, 1.451 mmol) was dissolved in a 4 mol/L hydrochloricacid-dioxane solution (3.5 mL). The mixture was stirred for 20 hours.Water (3.5 mL) was added thereto. After stirring for 2 hours, thesaturated aqueous solution of sodium hydrogen carbonate was addedthereto. The aqueous layer was extracted with ethyl acetate. The organiclayer was washed by water and brine. The organic layer was dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol) to give the crude product ofCompound 33 (448.2 mg).

Condition [1]: Retention time=1.09 (minutes): [M+H]=292.0

Step 5

The crude product of Compound 33 (140 mg, 0.48 mmol) obtained in thestep 4 was dissolved in tetrahydrofuran (2.8 mL), and cooled to −78° C.A phenylmagnesium bromide-tetrahydrofuran solution (9.6 mL, 9.6 mmol)was added thereto. The mixture was stirred for 9 hours. The mixture washeated to room temperature. The aqueous solution of saturated ammoniumchloride was added thereto. The mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica-gel column chromatography (chloroform-methanol)to give Compound 34 (124.4 mg, yield 70%).

Condition [1]: Retention time=1.63 (minutes): [M+H]=370.1

Step 6

Compound 34 (50 mg, 0.135 mmol) was dissolved in dichloromethane (1 mL).Triphenylphosphine (78 mg, 0.297 mmol), triethylamine (0.047 mL, 0.338mmol), and iodine (75 mg, 0.297 mmol) were added thereto. The mixturewas stirred for 1 hour. A 10% aqueous solution of sodium thiosulfate wasadded thereto. The mixture was stirred for a while. The aqueous layerwas extracted with chloroform. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol) to give Compound 1-0007 (7.5 mg,yield 16%).

¹H-NMR (CDCl₃) δ: 1.69 (s, 3H), 2.12-2.17 (m, 1H), 2.63-2.73 (m, 1H),2.94 (dd, J=17.2, 8.7 Hz, 1H), 3.05-3.15 (m, 1H), 5.42 (s, 1H), 5.63 (d,J=8.8 Hz, 1H), 6.58 (dd, J=6.7, 2.4 Hz, 1H), 6.98-7.04 (m, 2H), 7.20 (d,J=7.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.37 (t, J=6.8 Hz, 2H).

Example 6 Synthesis of Compound I-0009

Step 1

Under nitrogen atmosphere, para-methoxybenzyl alcohol (0.403 mL, 3.25mmol) was dissolved in tetrahydrofuran (2 mL). Under ice cooling, sodiumhydride (0.136 mg, 3.40 mmol) was added thereto. The mixture was heatedto room temperature, and stirred for 0.5 hours. Under ice cooling,Compound 35 (600 mg, 3.09 mmol) was added thereto. The mixture washeated to room temperature, stirred for 1.5 hours, and cooled to roomtemperature. The aqueous solution of saturated ammonium chloride wasadded thereto. The aqueous layer was extracted with chloroform. Theorganic layer was washed by brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica-gel column chromatography (hexane-ethylacetate), and suspended in diisopropyl ether for washing to giveCompound 36 (588.4 mg, yield 64%).

¹H-NMR (DMSO-DG) δ: 7.42 (2H, d, J=8.7 Hz), 6.95 (2H, d, J=8.7 Hz), 6.79(2H, s), 5.29 (2H, s), 3.76 (3H, s), 3.59 (3H, s).

Step 2

Under nitrogen atmosphere, Compound 24 (700 mg, 3.57 mmol) was dissolvedin tetrahydrofuran (7 mL). Under ice cooling, sodium hydride (0.157 mg,3.92 mmol) was added thereto. The mixture was heated to roomtemperature, and stirred for 0.5 hours. Under ice cooling, Compound 36(703 mg, 2.378 mmol) was added thereto. After stirring at 60° C. for 1hour, the mixture was cooled to room temperature. The aqueous solutionof saturated ammonium chloride was added thereto. The aqueous layer wasextracted with chloroform. The organic layer was washed by brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (10% dichloromethane contain hexane-ethyl acetate) togive the crude product of Compound 37.

Condition [1]: Retention time=2.31 (minutes): [M+H]=456.2

Step 3

Under nitrogen atmosphere, the crude product of Compound 37 (300 mg,0.659 mmol) obtained in the step 2, Pd₂(dba)₃ (121 mg, 0.132 mmol),BINAP (164 mg, 0.263 mmol), sodium tert-butoxide (0.127 g, 1.317 mmol),and 1-bromo-3-chloro-2-methyl benzene (203 mg, 0.988 mmol) weresuspended in toluene (3 mL). The mixture was stirred at 100° C. for 2hours. After cooling, the mixture was diluted with water. The aqueouslayer was extracted with ethyl acetate. The organic layer was washed bybrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to give thecrude product of Compound 38 (273.5 mg, yield 49%).

Condition [1]: Retention time=3.04 (minutes): [M+H]=580.2

Step 4

The crude product of Compound 38 (265 mg, 0.457 mmol) obtained in thestep 3 was dissolved in a 4 mol/L hydrochloric acid-dioxane solution(2.65 mL). The mixture was stirred for 1 hour. The solvent wasevaporated under reduced pressure. The residue was purified bysilica-gel column chromatography (hexane-ethyl acetate) to give Compound39 (106.4 mg, yield 81%).

Condition [1]: Retention time=1.78 (minutes): [M+H]=416.1

Step 5

Compound 39 (92 mg, 0.221 mmol) was dissolved in dichloromethane (1 mL).Triphenylphosphine (128 mg, 0.487 mmol), triethylamine (0.077 mL, 0.553mmol), and iodine (124 mg, 0.487 mmol) were added thereto. The mixturewas stirred for 5 days. A 10% aqueous solution of sodium thiosulfate wasadded thereto. The mixture was stirred for a while. The aqueous layerwas extracted with chloroform. The solvent was evaporated under reducedpressure. The residue was purified by silica-gel column chromatography(chloroform) to give Compound I-0009 (13.7 mg, yield 16%).

¹H-NMR (CDCl₃) δ: 1.59 (s, 3H), 2.25 (dq, J=14.0, 2.4 Hz, 1H), 2.63-2.73(m, 1H), 3.79 (s, 3H), 4.18-4.25 (m, 1H), 4.46-4.50 (m, 1H), 6.01 (s,1H), 6.52 (dd, J=7.3, 2.0 Hz, 1H), 6.98-7.04 (m, 2H), 7.21 (d, J=7.0 Hz,2H), 7.33 (t, J=7.4 Hz, 1H), 7.41 (t, J=7.3 Hz, 2H).

Example 7 Synthesis of Compound I-0021

Step 1

Under nitrogen atmosphere, Compound 31 (2 g, 5.48 mmol),4,5-dimethoxy-2-methylaniline (1.375 mg, 8.22 mmol), palladium acetate(123 mg, 0.548 mmol), Xantphos (476 mg, 0.822 mmol), and cesiumcarbonate (5.36 g, 16.45 mmol) were suspended in 1,4-dioxane (20 mL).The mixture was stirred at 110° C. for 4 hours. After cooling, themixture was diluted with water, and extracted with chloroform. Theorganic layer was washed by brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica-gel column chromatography (hexane-ethylacetate) to give Compound 40 (1.69 g, yield 62%).

Condition [1]: Retention time=1.70 (minutes): [M+H]=496.2

Step 2

Compound 40 (1.69 g, 3.41 mmol) was dissolved in a 4 mol/L hydrochloricacid-dioxane solution (17 mL). The mixture was stirred for 0.5 hours.Water (34 mL) was added thereto. The mixture was stirred for 5 hours.The saturated aqueous solution of sodium hydrogen carbonate was addedthereto for neutralization. The aqueous layer was extracted withchloroform. The organic layer was dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure to give thecrude product of Compound 41 (1.25 g).

Condition [1]: Retention time=0.70 (minutes): [M+H]=318.1

Step 3

The crude product of Compound 41 (150 mg, 0.473 mmol) obtained in thestep 2 was dissolved in tetrahydrofuran (1 mL). Under ice cooling, a3,4,5-trifluorophenylmagnesium bromide-tetrahydrofuran solution (7.88mL, 2.363 mmol) was added dropwise thereto. The mixture was heated toroom temperature, and stirred for 18 hours. A3,4,5-trifluorophenylmagnesium bromide-tetrahydrofuran solution (2.00mL, 0.591 mmol) was added dropwise thereto. The mixture was stirred for2 hours. The aqueous solution of saturated ammonium chloride was addedthereto. The mixture was stirred for a while, and extracted with ethylacetate. The organic layer was washed by brine, and dried over anhydroussodium sulfate. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol) to give Compound 42 (133 mg, yield63%).

Condition [1]: Retention time=1.53 (minutes): [M+H]=450.2

Step 4

Compound 42 (133 mg, 0.296 mmol) was dissolved in dichloromethane (2.6mL). Triphenylphosphine (171 mg, 0.651 mmol), triethylamine (0.103 mL,0.740 mmol), and iodine (165 mg, 0.651 mmol) were added thereto. Themixture was stirred for 5 days. A 10% aqueous solution of sodiumthiosulfate was added thereto. The mixture was stirred for a while. Theaqueous layer was extracted with chloroform. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica-gelcolumn chromatography (chloroform). The obtained solid was washed by amixed solvent of ethyl acetate and diisopropyl ether to give CompoundI-0021 (29.0 mg, yield 23%).

¹H-NMR (CDCl₃) δ: 1.72 (s, 3H), 2.08-2.13 (m, 1H), 2.63-2.74 (m, 1H),2.92-3.09 (m, 2H), 3.79 (s, 3H), 3.82 (s, 3H), 5.42 (s, 1H), 5.55 (d,J=8.8 Hz, 1H), 6.21 (s, 1H), 6.65 (s, 1H), 6.87 (t, J=7.0 Hz, 2H), 7.37(s, 1H).

Reference Example 2 Synthesis of Compound 45

Step 1

Compound 43 (2.2 g, 12.34 mmol) was dissolved in tetrahydrofuran (22mL). Tert-Butyl((tert-butoxycarbonyl))imino(1H-pyrazol-1-yl)methyl)carbamate (3.48 g, 11.22 mmol) and DIEA (3.92 mL, 22.44 mmol) were addedthereto. The mixture was stirred at 50° C. for 24 hours. After cooling,water was added thereto. The mixture was extracted with ethyl acetate.The organic layer was washed by brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to give Compound 44 (1.97 g, yield 42%).

Condition [1]: Retention time=2.75 (minutes): [M+H]=421.2

Step 2

Compound 44 (1.7 g, 4.04 mmol) was suspended in tert-butanol (136 mL).The mixture was stirred at 80° C. A 4 mol/L hydrochloric acid-dioxanesolution (34 mL) was added thereto. The mixture was stirred for 22hours. Ethanol (17 mL) was added thereto. The mixture was stirred for 24hours. After cooling, the solvent was evaporated under reduced pressure.The residue was washed by diethylether, and dried under reduced pressureto give Compound 45 (1.21 g, yield 96%).

Condition [1]: Retention time=0.57 (minutes): [M+H]=220.8

Example 8 Synthesis of Compound I-0036

Step 1

Compound 46 derived from 4-(4-fluorophenyl)-4-oxobutanoic acid wasreacted with Meldrum's acid according to the condition of the literature(Synlett 1993, 9, 651.) to give Compound 47.

Step 2

Iodobenzene diacetate (1.323 g, 4.11 mmol) was dissolved in methanol (10mL). A boron trifluoride-ethyl ether complex (0.521 mL, 4.11 mmol) wasadded thereto. The mixture was stirred at room temperature for 10minutes. A methanol (10 mL) solution of Compound 47 (2 g, 3.73 mmol) wasadded thereto. The mixture was stirred for 4 hours. The reaction mixturewas poured into the saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica-gel column chromatography (hexane-ethyl acetate) to giveCompound 48 (1.107 g, yield 57%).

Condition [2]: Retention time=3.54 (minutes): [M+H]=522

Step 3

Compound 48 (15.44 g, 34.3 mmol) was suspended in a mixed solvent ofmethanol (45 mL) and tetrahydrofuran (45 mL). A 2 mol/L aqueous solutionof sodium hydroxide (20.56 mL, 41.1 mmol) was added thereto. The mixturewas stirred at 60° C. for 1 hour. After cooling, a 2 mol/L hydrochloricacid solution (22 mL) was added thereto, and poured into brine. Theaqueous layer was extracted with ethyl acetate. The organic layer waswashed by brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure to give Compound 49 (15.13 g,yield 95%).

Condition [2]: Retention time=3.10 (minutes): [M+H]=435

Step 4

Compound 45 (1.21 g, 4.71 mmol) was suspended in methanol (24 mL).Potassium-tert-butoxide (1.058 g, 9.43 mmol), Compound 49 (2.463 g, 4.71mmol), and methanol (75 mL) were added thereto. The mixture was stirredat 80° C. for 6 hours, and cooled. The solvent was evaporated underreduced pressure. Methanol (24.6 mL) and potassium-tert-butoxide (0.529g, 4.712 mmol) were added thereto. The mixture was stirred at 80° C. for2 hours and 45 minutes. After cooling, Compound 41 (2.463 g, 4.71 mmol)and methanol (3 mL) were added thereto. The mixture was stirred at 80°C. for 3 hours. After cooling, water was added thereto. The aqueouslayer was extracted with ethyl acetate. The organic layer was washed bybrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the crude product of Compound50 (5.02 g).

Condition [1]: Retention time=3.05 (minutes): [M+H]=693.3

Step 5

The crude product of Compound 50 (5.02 g) obtained in the step 4 wasdissolved in tetrahydrofuran (25 mL). A TBAF-tetrahydrofuran solution(9.438 mL, 9.44 mmol) was added thereto. The mixture was stirred at roomtemperature for 12 hours. Thereafter, the mixture was stirred at 50° C.for 1 hour. After cooling, water was added thereto. The aqueous layerwas extracted with chloroform. The organic layer was washed by brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica-gelcolumn chromatography (chloroform-methanol) to give Compound 51 (937.4mg, yield 44%).

Condition [1]: Retention time=1.65 (minutes): [M+H]=455.3

Step 6

Compound 51 (930 mg, 2.046 mmol) was dissolved in dichloromethane (18.6mL). Triphenylphosphine (1181 mg, 4.50 mmol), triethylamine (1.426 mL,10.23 mmol), and iodine (1143 mg, 4.50 mmol) were added thereto. Themixture was stirred for 1 hour. A 10% aqueous solution of sodiumthiosulfate was added thereto. The mixture was stirred for a while. Theaqueous layer was extracted with chloroform. The solvent was evaporatedunder reduced pressure. The residue was purified by silica-gel columnchromatography (chloroform-methanol). The obtained racemate wassubjected to preparative SFC (Preparative condition 1) to separate anoptically active form. The obtained amorphous form was dissolved inethanol. Diisopropyl ether was slowly added thereto. The precipitatedsolids were filtered, and dried under reduced pressure to give Compound1-0036 (117.1 mg, yield 13%).

¹H-NMR (CDCl₃) δ: 1.77 (s, 3H), 2.12-2.17 (m, 1H), 2.65-2.75 (m, 1H),2.78 (s, 3H), 3.05-3.19 (m, 2H), 3.82 (s, 3H), 5.63 (d, J=8.6 Hz, 1H),7.07-7.09 (m, 2H), 7.19-7.22 (m, 2H), 7.43 (brs, 1H), 7.67 (brs, 1H).

Example 9 Synthesis of Compound I-0059

Step 1

Under nitrogen atmosphere, Compound 31 (1.918 g, 5.26 mmol),2-ethyl-6-methoxypyridin-3-amine (400 mg, 2.63 mmol), palladium acetate(59 mg, 0.263 mmol), Xantphos (228 mg, 0.394 mmol), and cesium carbonate(2.569 g, 7.88 mmol) were suspended in 1,4-dioxane (20 mL). The mixturewas stirred at 110° C. for 3 hours. After cooling, the mixture wasdiluted with water, and extracted with chloroform. The organic layer wasdried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (hexane-ethyl acetate) to give Compound 52 (685.0 mg,yield 54%).

Condition [1]: Retention time=2.01 (minutes): [M+H]=481.3

Step 2

The compound 52 (680 mg, 1.415 mmol) was suspended in a 4 mol/Lhydrochloric acid-dioxane solution (6.8 mL). The mixture was stirred for20 minutes. Water (6.8 mL) was added thereto. The mixture was stirredfor 6 hours. The reaction mixture was washed by ethyl acetate. Thesaturated aqueous solution of sodium hydrogen carbonate was added to theaqueous layer for neutralization. The mixture was extracted with 10%methanol-containing chloroform. The organic layer was dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the crude product of Compound 53 (465 mg).

Condition [1]: Retention time=0.79 (minutes): [M+H]=303.2

Step 3

The crude product of Compound 53 (465 mg) obtained in the step 2 wassuspended in tetrahydrofuran (4 mL). Under ice cooling, a3,5-difluorophenylmagnesium bromide-tetrahydrofuran solution (14.15 mL,7.07 mmol) was added dropwise thereto. The mixture was heated to roomtemperature, and stirred for 4 hours. The aqueous solution of saturatedammonium chloride was added thereto. The mixture was stirred for awhile, and extracted with ethyl acetate. The organic layer was washed bybrine, and dried over anhydrous magnesium sulfate. The obtained residuewas purified by silica-gel column chromatography (chloroform-methanol)to give Compound 54 (457.8 mg, yield 78%). Condition [1]: Retentiontime=1.62 (minutes): [M+H]=417.2

Step 4

Compound 54 (450 mg, 0.983 mmol) was dissolved in dichloromethane (4.5mL). Triphenylphosphine (387 mg, 1.475 mmol), triethylamine (0.343 mL,2.458 mmol), and iodine (374 mg, 1.475 mmol) were added thereto. Themixture was stirred for 15 hours. A 10% aqueous solution of sodiumthiosulfate was added thereto. The mixture was stirred for a while. Theaqueous layer was extracted with chloroform. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica-gelcolumn chromatography (chloroform-methanol). The obtained racemate wassubjected to preparative SFC (Preparative condition 2) to separate anoptically active form. The obtained amorphous form was solidified indiisopropyl ether. The precipitated solids were filtered, and driedunder reduced pressure to give Compound I-0059 (74.4 g, yield 19%).

¹H-NMR (CDCl₃) δ: 0.92 (t, J=7.4 Hz, 3H), 2.10-2.18 (m, 3H), 2.64-2.75(m, 1H), 2.93-3.11 (m, 2H), 3.87 (s, 3H), 5.43 (s, 1H), 5.58 (d, J=8.8Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 6.73-6.79 (m, 3H), 6.91 (d, J=8.5 Hz,1H), 7.30 (brs, 1H).

Example 10 Synthesis of Compound I-0086

Step 1

Under nitrogen atmosphere, Compound 31 (5.5 g, 15.08 mmol),6-methoxy-2-methylpyridin-3-amine (2.5 g, 18.09 mmol), palladium acetate(338 mg, 1.508 mmol), Xantphos (1.308 g, 2.261 mmol), and cesiumcarbonate (14.74 g, 45.2 mmol) were suspended in 1,4-dioxane (55 mL).The mixture was stirred at 110° C. for 1 hour. After cooling, themixture was diluted with water, and extracted with ethyl acetate. Theorganic layer was washed by brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica-gel column chromatography (hexane-ethylacetate) to give Compound 55 (2.61 g, yield 37%).

Condition [1]: Retention time=1.81 (minutes): [M+H]=467.3

Step 2

Compound 55 (2.61 g, 5.59 mmol) was suspended in a 4 mol/L hydrochloricacid-dioxane solution (26 mL). The mixture was stirred for 30 minutes.Water (26 mL) was added thereto. After stirring for 16 hours, thereaction mixture was washed by ethyl acetate. The saturated aqueoussolution of sodium hydrogen carbonate was added to the aqueous layer forneutralization. The mixture was extracted with 10% methanol-containingchloroform. The organic layer was dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the crudeproduct of Compound 56 (1.95 g).

Condition [1]: Retention time=0.60 (minutes): [M+H]=289.2

Step 3

The crude product of Compound 56 (1.95 g) obtained in the step 2 wassuspended in tetrahydrofuran (4 mL). Under ice cooling, a3,5-difluorophenylmagnesium bromide-tetrahydrofuran solution (44.9 mL,22.46 mmol) was added dropwise thereto. The mixture was heated to roomtemperature, and stirred for 22 hours. The aqueous solution of saturatedammonium chloride was added thereto. The mixture was stirred for awhile, and extracted with ethyl acetate. The organic layer was washed bybrine, and dried over anhydrous magnesium sulfate. The obtained residuewas purified by silica-gel column chromatography (chloroform-methanol)to give Compound 57 (1.73 g, yield 77%). Condition [1]: Retentiontime=1.44 (minutes): [M+H]=403.2

Step 4

Compound 57 (1.37 g, 4.3 mmol) was dissolved in dichloromethane (17.3mL). Triphenylphosphine (2481 mg, 9.46 mmol), triethylamine (1.498 mL,10.75 mmol), and iodine (2401 mg, 9.46 mmol) were added thereto. Themixture was stirred for 12 hours. A 10% aqueous solution of sodiumthiosulfate was added thereto. The mixture was stirred for a while. Theaqueous layer was extracted with chloroform. The mixture was dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol). The obtained racemate wassubjected to preparative SFC (Preparative condition 3) to separate anoptically active form. The obtained amorphous form was solidified indiisopropyl ether. The precipitated solids were filtered, and driedunder reduced pressure to give Compound 1-0047 (234.5 mg, yield 14%).

¹H-NMR (CDCl₃) δ: 1.93 (s, 3H), 2.10-2.16 (m, 1H), 2.64-2.75 (m, 1H),2.92-3.11 (m, 2H), 3.86 (s, 3H), 5.44 (s, 1H), 5.59 (d, J=7.9 Hz, 1H),6.51 (d, J=8.4 Hz, 1H), 6.74-6.80 (m, 3H), 6.90 (d, J=8.5 Hz, 1H), 7.29(brs, 1H).

Step 5

Compound 1-0047 (1.5 g, 3.90 mmol) was suspended in DMF (30 mL). NBS(0.729 g, 4.10 mmol) was added thereto. The mixture was stirred at 60°C. for 1 hour. After cooling, water was added dropwise thereto. Theprecipitated solids were filtered, and washed by water and ethylacetate. The obtained solids were dried under reduced pressure to giveCompound 1-0086 (1.66 g, yield 92%).

¹H-NMR (CDCl₃) δ: 1.90 (s, 3H), 2.16-2.21 (m, 1H), 2.71-2.82 (m, 1H),2.92 (d, J=29.4 Hz, 1H), 3.07-3.21 (m, 2H), 3.86 (s, 3H), 5.69 (d, J=9.3Hz, 1H), 6.52 (d, J=8.5 Hz, 1H), 6.74-6.80 (m, 3H), 6.87 (d, J=8.5 Hz,1H), 7.45 (brs, 1H).

Example 11 Synthesis of Compound I-0087

Step 1

Under nitrogen atmosphere, Compound I-0086 (200 mg, 0.432 mmol),(1,1′-bis(di-tert-butylphosphino)ferrocene)palladium(II) dichloride(28.1 mg, 0.043 mmol), potassium carbonate (119 mg, 0.863 mmol), andtrimethylboroxine (0.302 mL, 2.159 mmol) were suspended in 1,4-dioxane(2 mL). The mixture was stirred at 110° C. for 2 hours. After cooling,the mixture was diluted with water, and extracted with ethyl acetate.The organic layer was washed by brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by amino silica-gel columnchromatography (10% dichloromethane containing hexane-ethyl acetate),and solidified in diisopropyl ether. The precipitated solids werefiltered, and dried under reduced pressure to give Compound 1-0087 (48.2mg, yield 28%).

¹H-NMR (CDCl₃) δ: 1.93 (s, 3H), 2.11-2.16 (m, 1H), 2.64-2.75 (m, 1H),2.93-3.10 (m, 2H), 3.86 (s, 3H), 5.44 (s, 1H), 5.59 (d, J=8.3 Hz, 1H),6.51 (d, J=8.8 Hz, 1H), 6.74-6.79 (m, 3H), 6.90 (d, J=8.3 Hz, 1H).

Reference Example 3 Synthesis of Compound 61

Step 1

Compound 59 derived from 4-(4-fluorophenyl)-4-oxobutanoic acid wasreacted with Meldrum's acid with reference to the literature (Synlett1993, 9, 651.) to give Compound 60.

Step 2

Compound 60 (15.0 g, 30.4 mmol) was dissolved in acetonitrile (300 mL).Selectfluor(registered trademark) (20.4 g, 54.8 mmol) was added thereto.The mixture was stirred at room temperature for 6 days. Ethyl acetateand the saturated aqueous solution of sodium hydrogen carbonate wereadded thereto. The mixture was extracted with ethyl acetate. The organiclayer was washed by water, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica-gel column chromatography (hexane-ethyl acetate)to give Compound 61 (5.65 g, yield 36%) as a viscous oil.

¹H-NMR (CDCl₃) δ: 1.04 (s, 9H), 1.80-2.10 (m, 2H), 2.30-2.70 (m, 2H),3.77 (s, 3H), 4.75 (m, 1H), 5.00 (dd, J=12.0 Hz, 49.2 Hz, 1H), 6.94 (m,2H), 7.10-7.50 (m, 10H), 7.65 (m, 2H).

Example 12 Synthesis of Compound I-0078

Step 1

5-Methoxy-2-methyl-3-nitropyridine (3.00 g, 17.8 mmol) was dissolved intetrahydrofuran (60 mL). Pearlman's catalyst (0.60 g) was added thereto.The mixture was subjected to catalytic reduction at room temperatureovernight. The reaction mixture was filtered. The solvent was evaporatedunder reduced pressure to give Compound 63 (2.48 g, quant.) as a solid.

¹H-NMR (CDCl₃) δ: 2.35 (s, 3H), 3.61 (brs, 2H), 3.80 (s, 3H), 6.51 (d,J=2.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H).

Step 2

Compound 63 (1.50 g, 10.9 mmol) andN,N′-bis(carbobenzoxy)-1H-pyrazole-1-carboxamidine (4.52 g, 11.9 mmol)were dissolved in tetrahydrofuran (23 mL). DIEA (1.82 g, 14.1 mmol) wasadded thereto. The mixture was stirred at room temperature overnight.The solvent was evaporated under reduced pressure. Diethylether wasadded to the obtained residue. The precipitated solids were filtered togive Compound 64 (4.23 g, yield 87%).

¹H-NMR (CDCl₃) δ: 2.50 (s, 3H), 3.83 (s, 3H), 5.14 (s, 2H), 5.26 (s,2H), 7.20-7.40 (m, 10H), 8.02 (s, 1H), 8.07 (s, 1H), 10.24 (s, 1H),11.88 (s, 1H).

Step 3

Compound 64 (4.00 g, 8.92 mmol) was dissolved in tetrahydrofuran (80mL). Pearlman's catalyst (0.80 g) was added thereto. The mixture wassubjected to catalytic reduction at room temperature for 8 hours. A 2mol/L hydrochloric acid-methanol solution (13.4 mL, 26.8 mmol) was addedthereto. The mixture was filtered. The solvent was evaporated underreduced pressure. Diethylether was added to the obtained residue. Theprecipitated solids were filtered to give Compound 65 (2.00 g, yield89%).

¹H-NMR (DMSO-d₆) δ: 2.49 (s, 3H), 3.91 (s, 3H), 7.71 (brs, 4H), 7.79 (s,1H), 8.38 (s, 1H), 10.20 (s, 1H).

Step 4

Compound 65 (337 mg, 1.33 mmol) and Compound 61 (400 mg, 0.78 mmol) weredissolved in methanol (8.0 mL). Tert-Butoxy potassium (308 mg, 2.74mmol) was added thereto. The mixture was stirred at 80° C. for 6 hours.Ethyl acetate and water were added thereto. The mixture was extractedwith ethyl acetate. The organic layer was washed by brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol) to give Compound 66 (292 mg, yield58%) as an amorphous material.

¹H-NMR (CDCl₃) δ: 1.01 (s, 9H), 2.04 (m, 2H), 2.26 (m, 2H), 2.51 (s,3H), 3.70 (s, 3H), 4.70 (t, J=5.6 Hz, 1H), 5.60 (s, 1H), 6.91 (t, J=8.8Hz, 2H), 7.10-7.50 (m, 10H), 7.62 (m, 2H), 8.01 (m, 2H).

Step 5

Compound 66 (290 mg, 0.46 mmol) was dissolved in tetrahydrofuran (3.0mL). A 1.0 mol/L TBAF-tetrahydrofuran solution (0.684 mL, 0.684 mmol)was added thereto. The mixture was stirred at 50° C. overnight. Ethylacetate and water were added thereto. The mixture was extracted withethyl acetate. The organic layer was washed by brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. Diethylether was added to the obtained residue. Theprecipitated solids were filtered to give Compound 67 (180 mg, yield98%). [M+H]=385: Condition [2]: Retention time=0.96 (minutes)

Step 6

Compound 67 (180 mg, 0.447 mmol) and triphenylphosphine (176 mg, 0.671mmol) were dissolved in dichloromethane (3.0 mL). Triethylamine (0.155mL, 1.12 mmol) and iodine (170 mg, 671 mmol) were added thereto. Themixture was stirred at room temperature overnight. Ethyl acetate and theaqueous solution of sodium thiosulfate were added thereto. The mixturewas extracted with ethyl acetate. The organic layer was washed by brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica-gelcolumn chromatography (chloroform-methanol) to give a racemate (129 mg).The racemate was optically resolved by preparative SFC (Preparativecondition 1) to give Compound I-0078 (54.0 mg, yield 31%) as a solid.

¹H-NMR (DMSO-d₆) δ: 1.84 (s, 3H), 2.08 (m, 1H), 2.77 (m, 1H), 3.00-3.20(m, 2H), 3.77 (s, 3H), 5.89 (s, 1H), 7.15 (s, 1H), 7.26 (brs, 4H), 8.04(s, 1H), 8.42 (s, 1H).

Reference Example 4 Synthesis of Compound 71

Step 1

Meldrum's acid (7.18 g, 49.8 mmol), 4-(3,5-difluorophenyl)-4-oxobutanoic acid (9.70 g, 45.3 mmol), and DMAP (0.553 g,4.53 mmol) were dissolved in dichloromethane (200 mL). EDC hydrochloride(9.55 g, 49.8 mmol) and triethylamine (15.7 mL, 113 mmol) were addedthereto. The mixture was stirred at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure. Ethyl acetate and a 2mol/L aqueous solution of hydrochloric acid were added to the obtainedresidue. The mixture was extracted with ethyl acetate. The organic layerwas washed by water, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. Ethyl acetate was addedto the obtained residue. The precipitated solids were filtered to giveCompound 69 (10.2 g, yield 66%).

¹H-NMR (CDCl₃) δ: 1.78 (s, 6H), 3.38 (t, J=6.4 Hz, 2H), 3.56 (t, J=6.4Hz, 2H), 7.05 (m, 1H), 7.49 (m, 2H), 15.58 (s, 1H).

Step 2

Compound 69 (2.09 g, 6.14 mmol) was dissolved in acetonitrile (40 mL).Selectfluor(registered trademark) (2.41 g, 6.45 mmol) was added thereto.The mixture was stirred at room temperature overnight. Methanol (100 mL)and water (10 mL) were added thereto. The mixture was stirred at 80° C.for 1.5 hours. The solvent was evaporated under reduced pressure. Waterwas added to the obtained residue. The mixture was extracted with ethylacetate. The organic layer was washed by brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was purified by silica-gel column chromatography(hexane-ethyl acetate) to give Compound 70 (572 mg, yield 32%) as anoil.

¹H-NMR (CDCl₃) δ: 3.08 (m, 2H), 3.31 (m, 2H), 3.91 (s, 3H), 5.39 (d,J=49.2 Hz, 1H), 7.04 (m, 1H), 7.47 (m, 2H).

Step 3

Compound 70 (0.611 g, 2.12 mmol) was dissolved in methanol (12 mL), and10% palladium carbon (60.0 mg) was added thereto. The mixture wassubjected to catalytic reduction at room temperature for 3 hours. Thereaction mixture was filtered through Celite. The solvent was evaporatedunder reduced pressure to give the crude product of Compound 71 (616 mg,quant.) as an oil.

Example 13 Synthesis of Compound I-0099

Step 1

1-Fluoro-2-methoxy-5-methyl-aniline (1.67 g, 10.8 mmol) and cyanamide(1.36 g, 32.3 mmol) were dissolved in ethanol (20 mL). A 69% aqueoussolution of nitric acid (2.09 mL, 32.3 mmol) was added thereto. Themixture was stirred at 100° C. overnight. The solvent was evaporatedunder reduced pressure. Ethanol was added to the obtained residue. Theprecipitated solids were filtered to give Compound 73 (1.31 g, yield47%).

¹H-NMR (DMSO-d6) δ: 2.12 (s, 3H), 3.82 (s, 3H), 7.03 (d, J=8.4 Hz, 1H),7.17 (brs, 4H), 7.23 (d, J=12.0 Hz, 1H), 9.03 (brs, 1H).

Step 2

Compound 73 (0.305 g, 1.17 mmol) and the crude product of Compound 71(0.200 g, 0.689 mmol) obtained in Reference Example 4 were dissolved inmethanol (4.0 mL). Potassium tert-butoxide (0.155 g, 13.8 mmol) wasadded thereto. The mixture was stirred at 80° C. for 4 hours. Water wasadded thereto. The mixture was extracted with ethyl acetate. The organiclayer was washed by brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica-gel column chromatography (chloroform-methanol)to give Compound 74 (0.193 g, yield 64%) as an amorphous material.

[M+H]=438: Condition [2]: Retention time=1.88 (minutes)

Step 3

Compound 74 (180 mg, 0.447 mmol) and triphenylphosphine (176 mg, 0.671mmol) were dissolved in dichloromethane (3.0 mL). Triethylamine (0.155mL, 1.12 mmol) and iodine (170 mg, 671 mmol) were added thereto. Themixture was stirred at room temperature overnight. Ethyl acetate and theaqueous solution of sodium thiosulfate were added thereto. The mixturewas extracted with ethyl acetate. The organic layer was washed by brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica-gelcolumn chromatography (chloroform-methanol) to give a racemate (129 mg).The racemate was optically resolved by preparative SFC (Preparativecondition 2) to give the compound I-0099 (54.0 mg, yield 31%) as asolid.

¹H-NMR (DMSO-d₆) δ: 1.71 (s, 3H), 2.13 (m, 1H), 2.77 (m, 1H), 3.08 (m,2H), 3.75 (s, 3H), 5.83 (s, 1H), 6.80-7.10 (m, 4H), 7.23 (t, J=8.8 Hz,1H), 8.37 (s, 1H).

Example 14 Synthesis of Compound I-0103

Step 1

Under nitrogen atmosphere, Compound 75 (500 mg, 2.83 mmol) was dissolvedin dioxane (5 mL). 2-Methylamino-1-phenylethan-1-ol (514 mg, 3.40 mmol)was added thereto. The mixture was stirred at 130° C. for 1 hour undermicrowave irradiation. Water was added thereto. The mixture wasextracted with ethyl acetate. The organic layer was washed by brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol) to give Compound 76 (358 mg, yield43%).

Condition [1]: Retention time=1.38 (minutes): [M+H]=292.2

Step 2

Compound 76 (312 mg, 1.071 mmol) was dissolved in dichloromethane (5mL). Triphenylphosphine (421 mg, 1.606 mmol), triethylamine (0.371 mL,2.68 mmol), and iodine (408 mg, 1.606 mmol) were added thereto. Themixture was stirred at room temperature for 4 hours. The solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica-gel column chromatography (chloroform-methanol) to give Compound77 (278 mg, yield 95%).

Condition [1]: Retention time=1.27 (minutes): [M+H]=274.1

Step 3

Propionic acid (0.5 mL) and 2,5-dimethyl benzothiazol-6-amine (68.5 mg,0.384 mmol) were added to Compound 77 (30 mg, 0.22 mmol). The mixturewas stirred at 140° C. for 1 hour. The solvent was evaporated underreduced pressure. The residue was purified by reverse-phase columnchromatography to give Compound I-0103 (9 mg, yield 20%).

Condition [3]: Retention time=1.40 (minutes): [M+H]=404

Example 15 Synthesis of Compound I-0107

Step 1

Under nitrogen atmosphere, phosphorus oxychloride (0.5 mL) was added toCompound 78 (150 mg, 0.547 mmmol). The mixture was stirred at 80° C. for30 minutes. The solvent was evaporated under reduced pressure to givethe crude product of Compound 79.

Step 2

The crude product of Compound 79 obtained in the step 1 was dissolved indioxane (1.5 mL). 2-Amino-1-phenylethan-1-ol (90 mg, 0.656 mmol) wasadded thereto. The mixture was stirred at 130° C. for 30 minutes undermicrowave irradiation. Water was added thereto. The mixture wasextracted with ethyl acetate. The organic layer was washed by brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give the crude product of Compound 80.

Step 3

The crude product of Compound 80 obtained in the step 2 was dissolved inDMF (1 mL). Potassium carbonate (92 mg, 0.666 mmol) was added thereto.The mixture was stirred at 50° C. for 30 minutes. Water was addedthereto. The mixture was extracted with ethyl acetate. The organic layerwas washed by brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by reverse-phase column chromatography to give Compound 1-0107(23.6 mg, yield 12%).

Condition [1]: Retention time=1.39 (minutes): [M+H]=376

Example 16 Synthesis of Compound I-0145

Step 1: Synthesis of Compound 82

Methyl 3-amino-4-methylbenzoate (3.85 g, 23.3 mmol) and Compound 81 (3.0g, 15.5 mmol, refer to International Publication WO 2012/020749A for thesynthesis method) were added to N-methylpyrrolidone (21 mL). The mixturewas stirred at 130° C. for 26 hours. The reaction mixture was pouredinto water (210 mL). Under ice cooling, the mixture was stirred for 30minutes. The precipitated solids were filtered, washed by water anddiisopropyl ether, and dried under reduced pressure to give Compound 82(4.20 g, yield 93.2%).

¹H-NMR (DMSO-d₆) δ: 2.28 (s, 3H), 3.08 (s, 3H), 3.85 (s, 3H), 7.41 (d,J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 8.09 (s, 1H), 8.59-8.68 (br, 1H),11.28-11.36 (br, 1H).

Step 2: Synthesis of Compound 83

Under nitrogen atmosphere, Compound 82 (4.11 g, 14.2 mmol) was suspendedin acetonitrile (41 ml). DIEA (5.44 ml, 31.1 mmol) and a phosphonitrilicchloride trimer (5.17 g, 14.9 mmol) were added thereto. The mixture wasstirred at room temperature for 3.5 hours.(±)-2-Amino-1-(3,4,5-trifluorophenyl)ethanol (2.98 g, 15.6 mmol) wasadded thereto. The mixture was stirred at room temperature for 2 hours.The saturated aqueous solution of sodium hydrogen carbonate was addedthereto. The mixture was extracted with ethyl acetate. The organic layerwas washed by brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure to give the crude productof Compound 83.

Condition [1]: Retention time=1.44 (minutes): [M+H]=464.2

Step 3: Synthesis of Compound I-0215

Under nitrogen atmosphere, the crude product of Compound 83 obtained inthe step 2 was suspended in dichloromethane (120 mL). Triphenylphosphine(6.30 g, 24.0 mmol), triethylamine (7.83 ml, 56.5 mmol), and iodine(6.10 g, 24.0 mmol) were added thereto. The mixture was stirred at roomtemperature for 45 minutes. The saturated aqueous solution of sodiumhydrogen carbonate was added thereto. The mixture was extracted withchloroform. The organic layer was washed by a 10% aqueous solution ofsodium thiosulfate and brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas purified by silica-gel column chromatography (chloroform-methanol)to give Compound I-0215 (2.70 g, yield 42.9%).

¹H-NMR (CDCl₃) δ: 1.80 (s, 3H), 3.37 (s, 3H), 3.83 (dd, J=14.3, 5.8 Hz,1H), 3.87 (s, 3H), 4.44 (dd, J=14.3, 10.5 Hz, 1H), 5.37 (dd, J=10.2, 5.9Hz, 1H), 7.01 (t, J=7.0 Hz, 2H), 7.10 (s, 1H), 7.20 (d, J=7.8 Hz, 1H),7.33 (s, 1H), 7.55 (dd, J=7.9, 1.4 Hz, 1H).

Step 4: Synthesis of Compound I-0216

The compound I-0215 (2.7 g, 6.06 mmol) was dissolved in a mixed solutionof methanol (13.5 ml) and tetrahydrofuran (27 ml). A 1 mol/L aqueoussolution of sodium hydroxide (18.2 ml, 18.2 mmol) was added thereto. Themixture was stirred at room temperature for 6.5 hours. The reactionmixture was diluted with water, and washed by diethylether. The aqueouslayer was adjusted to pH 4 using a 2 mol/L aqueous solution ofhydrochloric acid. The mixture was extracted with ethyl acetate. Theorganic layer was washed by brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give thecrude product of Compound I-0216.

Condition [1]: Retention time=1.42 (minutes): [M+H]=432.7

Step 5: Synthesis of Compound I-0217

DMF (28 mL), ammonium chloride (386 mg, 7.22 mmol), HOBt (975 mg, 7.22mmol), triethylamine (1.0 mL, 7.22 mmol), and EDC (1.38 g, 7.22 mmol)were added to the crude product of Compound I-0216. The mixture wasstirred at room temperature for 2 hours. Water was added to the reactionmixture. The aqueous layer was adjusted to pH 4 using a 2 mol/L aqueoussolution of hydrochloric acid. The mixture was extracted with ethylacetate. The organic layer was washed by the saturated aqueous solutionof sodium hydrogen carbonate and brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. Diethyletherwas added to the obtained residue. The solids were filtered to giveCompound 1-0217 (2.11 g, yield 81.5%).

¹H-NMR (CDCl₃) δ: 1.80 (s, 3H), 3.38 (s, 3H), 3.82 (dd, J=14.4, 5.9 Hz,1H), 4.44 (dd, J=14.4, 10.4 Hz, 1H), 5.37 (dd, J=10.5, 6.0 Hz, 1H),5.50-5.75 (br, 1H), 5.86-6.10 (br, 1H), 7.01 (t, J=7.0 Hz, 2H), 7.14 (s,1H), 7.19 (d, J=8.0 Hz, 1H), 7.32-7.38 (m, 2H).

Step 6: Synthesis of Compound I-0145

Pyridine (17 mL) was added to Compound 1-0217 (2.1 g, 4.88 mmol). Underice cooling, trifluoroacetic acid anhydride (1.72 ml, 12.2 mmol) wasadded dropwise thereto. The mixture was stirred for 4 hours. Water wasadded to the reaction mixture. The aqueous layer was adjusted to pH 4using a 2 mol/L aqueous solution of hydrochloric acid. The mixture wasextracted with ethyl acetate. The organic layer was washed by thesaturated aqueous solution of sodium hydrogen carbonate and brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue was purified by silica-gel columnchromatography (chloroform-methanol), and optically resolved by SFC(liquid carbon dioxide-isopropanol) to give Compound I-0145 (725 mg,yield 36.0%).

¹H-NMR (CDCl₃) δ: 1.79 (s, 3H), 3.36 (s, 3H), 3.84 (dd, J=14.4, 5.9 Hz,1H), 4.45 (dd, J=14.4, 10.4 Hz, 1H), 5.35 (dd, J=10.3, 5.8 Hz, 1H), 6.92(s, 1H), 6.99 (t, J=7.0 Hz, 2H), 7.22-7.29 (m, 2H).

Reference Example 5 Synthesis of Compound 88

Synthetic Procedures for Seed crystal

(10R)-(−)-Camphorsulfonic acid (1.276 g, 5.49 mmol) was added to a mixedsolution of Compound 87 (1.0 g, 5.23 mmol) in ethyl acetate (24.33 mL)and water (0.678 mL) at room temperature under stirring, and dissolvedtherein. The mixture was stirred at room temperature for 1 hour. Theprecipitated solids were filtered to give Compound 88 (0.543 g, yield24.5%, optical purity 91.8% ee).

Step 1

(10R)-(−)-Camphorsulfonic acid (96.63 g, 416 mmol) was added to asolution of Compound 87 (75.65 g, 396 mmol) in ethyl acetate (1841 mL)and water (51.3 mL) at room temperature under stirring, and dissolvedtherein. A small amount of seed crystal was added thereto. The mixturewas stirred for 1 hour. The precipitated solids were filtered to givethe crude Compound 88 (48.20 g). A small amount of seed crystal wasadded to a solution of the crude Compound 88 in ethyl acetate (1841 mL)and water (51.3 mL) at room temperature under stirring. The mixture wasstirred for 1 hour. The precipitated solids were filtered to giveCompound 88 (17.4 g, yield 10%, optical purity 99.5% ee).

¹H-NMR (DMSO-d₆) δ: 0.75 (s, 3H), 1.05 (s, 3H), 1.29 (m, 2H), 1.80 (d,J=18.0 Hz, 1H), 1.86 (m, 1H), 1.94 (t, J=4.4 Hz, 1H), 2.20-2.30 (m, 1H),2.38 (d, J=14.8 Hz, 1H), 2.69 (m, 1H), 2.88 (d, J=14.8 Hz, 1H), 2.88(dd, J=12.8, 8.8 Hz, 1H), 3.10 (dd, J=12.8, 8.8 Hz, 1H), 4.82 (m, 1H),6.34 (d, J=4.0 Hz, 1H), 7.36 (m, 2H), 7.85 (brs, 3H).

Retention time: 7.1 minutes

Column: CHIRALPAK ID-3, 4.6/SFC (3 μm 150×4.6 mm) (DAICEL)

Flow rate: 0.8 mL/min

UV detection wavelength: 210 nm

Mobile phases: [A] is a 10 mmol/L ammonium bicarbonate buffer (pH9), and[B] is acetonitrile.

Gradient: linear gradient of 10%-90% solvent [B] was performed for 17minutes, and 90% solvent [B] was maintained for 5 minutes.

Example 17 Synthesis of Compound I-0168

Step 1

Methyl 3-amino-4-methyl-6-fluorobenzoate was added to a suspension ofCompound 81 (5.00 g, 25.9 mmol) in N-methylpyrrolidone (35 mL) at roomtemperature. The mixture was stirred at 120° C. for 13 hours. Thereaction mixture was added dropwise to water (210 mL). The precipitatedsolids were filtered, and washed by water and isopropanol. The obtainedsolids were air-dried to give Compound 89 (6.92 g, yield 87%).

1H-NMR (DMSO-d6) δ: 2.25 (s, 3H), 3.07 (s, 3H), 3.84 (s, 3H), 7.31 (d,J=11.5 Hz, 1H), 7.90 (brs, 1H), 8.64 (brs, 1H), 11.28 (brs, 1H).

Step 2

A phosphonitrilic chloride trimer (2.83 g, 8.14 mmol) was added to amixed solution of Compound 89 (2.39 g, 7.75 mmol) obtained in the step 1in acetonitrile (23.9 mL) and N,N-diisopropylethylamine (2.98 mL, 17.06mmol) at room temperature. The mixture was stirred at room temperaturefor 90 minutes. Compound 88 (3.61 g, 8.53 mmol) andN,N-diisopropylethylamine (2.98 mL, 17.06 mmol) were added thereto. Themixture was stirred at room temperature for 90 minutes. Saturated sodiumhydrogen carbonate was added thereto. The mixture was stirred. Thereaction mixture was filtered through Celite. The mixture was extractedwith ethyl acetate. The organic layer was washed by water and brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The obtained residue (7.36 g) was dissolved inchloroform (66.2 mL) and methanol (7.4 mL). Amino silica-gel (73.6 g)was added thereto. The mixture was stirred at room temperature. Aminosilica-gel was washed by chloroform and methanol (9:1). The solvent wasevaporated under reduced pressure to give the crude product of Compound90 (3.32 g).

Condition [1]: Retention time=1.33 (minutes): [M+H]=482.15

Step 3

The crude product of Compound 90 (3.32 g, 6.00 mmol) obtained in thestep 2 was dissolved in dichloromethane (100 mL). Trimethylaminehydrochloride (1.15 g, 12.00 mmol) was added thereto. Methanesulfonylchloride (1.40 mL, 18.00 mmol) and triethylamine (4.16 mL, 30.00 mmol)were added thereto at 0° C. The mixture was stirred at room temperaturefor 4 hours. The saturated aqueous solution of sodium hydrogen carbonatewas added thereto. The mixture was extracted with ethyl acetate. Theorganic layer was washed by water and brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theobtained residue was purified by silica-gel column chromatography(chloroform-methanol) to give Compound 1-0218 (1.12 g, yield 40%).

¹H-NMR (CDCl₃) δ: 1.77 (s, 3H), 3.33 (s, 3H), 3.81 (dd, J=14.3, 6.0 Hz,1H), 3.88 (s, 3H), 4.43 (dd, J=14.4, 10.4 Hz, 1H), 5.35 (dd, J=10.3, 6.0Hz, 1H), 7.01-6.92 (m, 3H), 7.23 (d, J=6.7 Hz, 1H), 7.23 (d, J=6.7 Hz,1H), 7.48 (brs, 1H).

Step 4

Under nitrogen atmosphere, Compound I-0218 (1.12 g, 2.42 mmol) obtainedin the step 3 was added to a suspension of lithium borohydride (263 mg,12.08 mmol) in tetrahydrofuran (13.44 mL) at 0° C. The mixture wasrefluxed by heating for 6 hours. Methanol and dilute hydrochloric acidwere added thereto at 0° C. The mixture was extracted with ethylacetate. The organic layer was washed by the saturated aqueous solutionof sodium hydrogen carbonate and brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica-gel column chromatography(chloroform-methanol) to give the compound 1-0168 (0.88 g, yield 84%).

¹H-NMR (CDCl₃) δ: 1.72 (s, 3H), 3.39 (s, 3H), 3.82 (dd, J=14.3, 6.0 Hz,1H), 4.43 (dd, J=14.3, 10.5 Hz, 1H), 4.63 (s, 2H), 5.36 (dd, J=10.3, 6.0Hz, 1H), 6.68 (d, J=7.0 Hz, 1H), 6.83 (d, J=10.5 Hz, 1H), 6.99 (t, J=7.0Hz, 2H), 7.24 (brs, 1H).

Example 18 Synthesis of Compound I-0171

Step 1: Synthesis of Compound 92

2-methyl-5-(2-acetoxyethoxy)aniline (23.4 g, 112 mmol, refer to J. Med.Chem. 2015, 58, 8413-8426 for the synthesis method) and Compound 81(19.6 g, 102 mmol) were added to tert-butanol (234 mL). The mixture wasstirred at 110° C. for 56 hours. The reaction mixture was poured intodiethylether (234 mL). The mixture was stirred for 5 minutes. Theprecipitated solids were filtered, washed by diethylether (234 mL), anddried under reduced pressure to give Compound 92 (24.2 g, yield 82.7%).

¹H-NMR (DMSO-DG) δ: 2.04 (s, 3H), 2.14 (s, 3H), 3.08 (s, 3H), 4.13 (t,J=4.5 Hz, 2H), 4.31 (t, J=4.5 Hz, 2H), 6.75 (dd, J=8.3, 2.5 Hz, 1H),7.15 (d, J=8.3 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 8.43 (s, 1H), 11.15 (s,1H).

Step 2: Synthesis of Compound 93

Under nitrogen atmosphere, Compound 92 (11.5 g, 34.4 mmol) was suspendedin acetonitrile (115 ml). N,N-Diisopropylethylamine (18.0 ml, 103 mmol)and a phosphonitrilic chloride trimer (12.6 g, 36.1 mmol) were addedthereto. The mixture was stirred at room temperature for 1.5 hours.Compound 88 (16.0 g, 37.8 mmol) and N,N-diisopropylethylamine (8.41 ml,48.2 mmol) were added thereto. The mixture was stirred at roomtemperature for 1 hour. Water (200 mL) was added thereto. The mixturewas extracted three times with ethyl acetate (200 mL). The organic layerwas washed by brine (300 mL), and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas dissolved in chloroform (332 mL) and methanol (36.8 mL). Aminosilica-gel (368 g) was added thereto. The mixture was stirred at roomtemperature. Amino silica-gel was washed by chloroform and methanol(9:1). The solvent was evaporated under reduced pressure to give thecrude product of Compound 93 (15.7 g, yield 89.9%).

Condition [1]: Retention time=1.36 (minutes): [M+H]=508.2

Step 3: Synthesis of Compound I-0219

The crude product of Compound 93 (14.1 g, 27.8 mmol) obtained in thestep 2 was dissolved in dichloromethane (282 mL). Trimethylaminehydrochloride (5.31 g, 55.6 mmol) was added thereto. Methanesulfonylchloride (6.50 mL, 83.0 mmol) and triethylamine (19.3 mL, 139 mmol) wereadded thereto at 0° C. The mixture was stirred at room temperature for 4hours. The saturated aqueous solution of sodium hydrogen carbonate wasadded thereto. The mixture was extracted with ethyl acetate. The organiclayer was washed by water and brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica-gel column chromatography(chloroform-methanol) to give Compound 1-0219 (7.18 g, yield 52.8%).

¹H-NMR (CDCl₃) δ: 1.68 (s, 3H), 2.10 (s, 3H), 3.40 (s, 3H), 3.82 (dd,J=14.4, 5.9 Hz, 1H), 4.09 (t, J=4.8 Hz, 2H), 4.38 (t, J=4.8 Hz, 3H),4.43 (dd, J=14.4, 10.4 Hz, 3H), 5.37 (dd, J=10.4, 5.9 Hz, 1H), 6.22 (d,J=2.3 Hz, 1H), 6.53-6.55 (m, 1H), 7.01 (dd, J=14.3, 7.8 Hz, 4H).

Step 4: Synthesis of Compound I-0171

Compound 1-0219 (7.25 g, 14.8 mmol) was dissolved in a mixed solution ofmethanol (36.3 ml) and tetrahydrofuran (36.3 ml). A 1 mol/L aqueoussolution of sodium hydroxide (22.2 ml, 22.2 mmol) was added thereto. Themixture was stirred at room temperature for 1 hour. Methanol andtetrahydrofuran were evaporated under reduced pressure. The obtainedaqueous solution was extracted with ethyl acetate. The organic layer waswashed by brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica-gel chromatography (chloroform-methanol) to give CompoundI-0171 (5.51 g, yield 83.1%).

1H-NMR (CDCl₃) δ: 1.67 (s, 3H), 2.05 (t, J=5.8 Hz, 1H), 3.39 (s, 3H),3.82 (dd, J=14.3, 5.8 Hz, 1H), 3.92 (m, 2H), 4.00 (m, 2H), 4.43 (dd,J=14.3, 10.3 Hz, 1H), 5.37 (dd, J=10.3, 5.8 Hz, 1H), 6.23 (d, J=2.3 Hz,1H), 6.55 (dd, J=8.3, 2.3 Hz, 1H), 7.01 (m, 3H), 7.12 (s, 1H).

The following compounds were synthesized according to the generalsynthetic procedures and the procedures described in Examples. Theirchemical structural formulas and physical properties (LC/MS data or NMRspectrum) are shown below.

In the following tables, the compound expressed as “a” in the column ofoptical activity is a mixture of an R form and an S form. The compoundexpressed as “b” in the column of optical activity is either an R formor an S form, through its stereoscopic information is unknown. Thecompound expressed as “c” in the column of optical activity indicatesthat its stereoscopy is determined as shown in the chemical structure.

TABLE 1 Reten- Com- tion LC/MS pound time condi- Optical No. Chemicalstructure NMR [M + H] (min) tion activity I-0001

1H-NMR (DMSO-d6) δ: 4.65 (dd, J = 8.8, 2.8 Hz, 1H), 4.97 (s, 1H), 5.12(t, J = 8.6 Hz, 1H), 5.79 (d, J = 6.1 Hz, 1H), 6.87 (br, 1H), 7.10 (dd,J = 8.3, 4.0 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.39-7.58 (m, 7H), 8.73(d, J = 3.6 Hz, 1H), 9.74 (br, 1H). 357 1.29 [4] a I-0002

1H-NMR (DMSO-d6) δ: 1.56 (s, 3H), 4.58 (d, J = 8.7 Hz, 1H), 4.93 (s,1H), 5.06 (t, J = 8.4 Hz, 1H), 5.66 (br, 1H), 6.53 (br, 1H), 6.96- 7.04(m, 2H), 7.30-7.44 (m, 5H), 9.58 (brs, 1H). 354 2.05 [4] a I-0003

1H-NMR (DMSO-d6) δ: 1.45 (s, 3H), 4.04 (d, J = 12.0 Hz, 1H), 4.23 (d, J= 10.2 Hz, 1H), 4.61 (d, J = 16.2 Hz, 1H), 4.75 (d, J = 16.2 Hz, 1H),5.33 (s, 1H), 5.47 (s, 1H), 6.47 (br, 1H), 6.95-7.03 (m, 2H), 7.23-7.29(m, 3H), 7.34-7.38 (m, 2H), 9.74 (br, 1H). 368 2.07 [4] b I-0004

332 1.68 [1] a I-0005

1H-NMR (CDCl3) δ: 1.53 (s, 3H), 1.65-1.78 (m, 2H), 2.17-2.34 (m, 2H),2.69-2.84 (m, 2H), 5.34 (s, 1H), 6.00 (dd, J = 5.0, 2.3 Hz, 1H), 6.49(dd, J = 6.9, 2.6 Hz, 1H), 6.97-7.03 (m, 2H), 7.15 (d, J = 7.3 Hz, 2H),7.28 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 3H). 366 2.18 [1] a

TABLE 2 I-0006

1H-NMR (CDCl3) δ: 1.60 (s, 3H), 2.24 (dd, J = 14.3, 2.8 Hz, 1H),2.62-2.71 (m, 1H), 3.72-3.79 (m, 1H), 4.16 (dt, J = 16.6, 6.1 Hz, 1H),4.32-4.36 (m, 1H), 4.99 (d, J = 2.0 Hz, 1H), 6.00 (d, J = 3.3 Hz, 1H),6.53 (dd, J = 7.0, 2.3 Hz, 1H), 6.98-7.04 (m, 2H), 7.22 (d, J = 6.3 Hz,2H), 7.33 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.0 Hz, 2H). 368 2.03 [1] aI-0007

1H-NMR (CDCl3) δ: 1.69 (s, 3H), 2.12-2.17 (m, 1H), 2.63-2.73 (m, 1H),2.94 (dd, J = 17.2, 8.7 Hz, 1H), 3.05-3.15 (m, 1H), 5.42 (s, 1H), 5.63(d, J = 8.8 Hz, 1H), 6.58 (dd, J = 6.7, 2.4 Hz, 1H), 6.98- 7.04 (m, 2H),7.20 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 6.8 Hz,2H). 352 1.82 [1] a I-0008

386 2.09 [1] a I-0009

1H-NMR (CDCl3) δ: 1.59 (s, 3H), 2.25 (dq, J = 14.0, 2.4 Hz, 1H),2.63-2.73 (m, 1H), 3.79 (s, 3H), 4.18-4.25 (m, 1H), 4.46-4.50 (m, 1H),6.01 (s, 1H), 6.52 (dd, J = 7.3, 2.0 Hz, 1H), 6.98-7.04 (m, 2H), 7.21(d, J = 7.0 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H).398 2.02 [1] a I-0010

378 1.27 [1] b

TABLE 3 I-0011

366 1.85 [1] b I-0012

418 2.18 [1] b I-0013

430 1.52 [1] b I-0014

348 1.3 [1] a I-0015

318 1.37 [1] a I-0016

348 1.46 [1] a

TABLE 4 I-0017

396 1.32 [1] a I-0018

396 1.33 [1] a I-0019

364 1.2 [1] a I-0020

362 1.45 [1] a I-0021

1H-NMR (CDCl3) δ: 1.72 (s, 3H), 2.08-2.13 (m, 1H), 2.63-2.74 (m, 1H),2.92-3.09 (m, 2H), 3.79 (s, 3H), 3.82 (s, 3H), 5.42 (s, 1H), 5.55 (d, J= 8.8 Hz, 1H), 6.21 (s, 1H), 6.65 (s, 1H), 6.87 (t, J = 7.0 Hz, 2H),7.37 (s, 1H). 432 1.55 [1] a

TABLE 5 I-0022

366 1.53 [1] a I-0023

366 1.4 [1] a I-0024

366 1.47 [1] a I-0025

414 1.39 [1] b I-0026

407 1.54 [1] a

TABLE 6 I-0027

381 1.82 [1] a I-0028

381 1.56 [1] a I-0029

389 1.47 [1] c I-0030

349 1.28 [1] a I-0031

392 1.56 [1] a I-0032

419 1.47 [1] a

TABLE 7 I-0033

400 1.83 [1] a I-0034

349 1.21 [1] a I-0035

349 1.2 [1] a I-0036

1H-NMR (CDCl3) δ: 1.77 (s, 3H), 2.12-2.17 (m, 1H), 2.65-2.75 (m, 1H),2.78 (s, 3H), 3.05-3.19 (m, 2H), 3.82 (s, 3H), 5.63 (d, J = 8.6 Hz, 1H),7.07-7.09 (m, 2H), 7.19- 7.22 (m, 2H), 7.43 (brs, 1H), 7.67 (brs, 1H).437 1.53 [1] b I-0037

400 1.55 [1] b

TABLE 8 I-0038

384 1.45 [1] b I-0039

376 1.55 [1] a I-0040

360 1.32 [1] a I-0041

384 1.48 [1] b I-0042

402 1.59 [1] b

TABLE 9 I-0043

363 1.49 [1] a I-0044

412 1.7 [1] a I-0045

396 1.52 [1] a I-0046

366 1.51 [1] a I-0047

385 1.38 [1] b

TABLE 10 I-0048

403 1.49 [1] b I-0049

366 1.36 [1] b I-0050

382 1.5 [1] b I-0051

399 1.64 [1] a I-0052

378 1.43 [1] a

TABLE 11 I-0053

425 1.71 [1] b I-0054

425 1.53 [1] b I-0055

399 1.5 [1] b I-0056

420 1.86 [1] b I-0057

438 1.78 [1] b

TABLE 12 I-0058

443 1.57 [1] b I-0059

1H-NMR (CDCl3) δ: 0.92 (t, J = 7.4 Hz, 3H), 2.10-2.18 (m, 3H), 2.64-2.75(m, 1H), 2.93-3.11 (m, 2H), 3.87 (s, 3H), 5.43 (s, 1H), 5.58 (d, J = 8.8Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.73-6.79 (m, 3H), 6.91 (d, J = 8.5Hz, 1H), 7.30 (brs, 1H). 399 1.56 [1] b I-0060

402 1.64 [1] b I-0061

384 1.71 [1] b I-0062

420 1.68 [1] b

TABLE 13 I-0063

402 1.74 [1] b I-0064

402 1.6 [1] b I-0065

398 1.79 [1] b I-0066

396 1.52 [1] b I-0067

378 1.37 [1] b

TABLE 14 I-0068

403 1.43 [1] b I-0069

385 1.38 [1] b I-0070

367 1.27 [1] b I-0071

385 1.06 [1] b I-0072

403 1.79 [1] b

TABLE 15 I-0073

414 1.51 [1] b I-0074

396 1.46 [1] b I-0075

413 1.71 [1] b I-0076

431 1.75 [1] b 1-0077

402 1.7 [1] b

TABLE 16 I-0078

385 0.99 [1] b I-0079

367 1.02 [1] b I-0080

399 1.5 [1] b I-0081

417 1.56 [1] b I-0082

417 1.96 [1] b

TABLE 17 I-0083

435 1.79 [1] b I-0084

403 1.8 [1] b I-0085

419 1.55 [1] b I-0086

1H-NMR (CDCl3) δ: 1.90 (s, 3H), 2.16-2.21 (m, 1H), 2.71-2.82 (m, 1H),2.92 (d, J = 29.4 Hz, 1H), 3.07-3.21 (m, 2H), 3.86 (s, 3H), 5.69 (d, J =9.3 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.74-6.80 (m, 3H), 6.87 (d, J =8.5 Hz, 1H), 7.45 (brs, 1H). 463 1.59 [1] b I-0087

1H-NMR (CDCl3) δ: 1.93 (s, 3H), 2.11-2.16 (m, 1H), 2.64-2.75 (m, 1H),2.93-3.10 (m, 2H), 3.86 (s, 3H), 5.44 (s, 1H), 5.59 (d, J = 8.3 Hz, 1H),6.51 (d, J = 8.8 Hz, 1H), 6.74-6.79 (m, 3H), 6.90 (d, J = 8.3 Hz, 1H).399 1.41 [1] b

TABLE 18 I-0088

389 1.16 [1] b I-0089

461 1.88 [1] b I-0090

421 1.89 [1] b I-0091

411 1.71 [1] b I-0092

413 1.57 [1] b

TABLE 19 I-0093

403 1.43 [1] b I-0094

419 1.87 [1] b I-0095

403 1.43 [1] b I-0096

431 1.76 [1] b I-0097

402 1.64 [3] b

TABLE 20 I-0098

402 1.74 [3] b I-0099

420 1.68 [1] b I-0100

390 1.38 [3] a I-0101

443 1.58 [1] b I-0102

414 1.52 [1] b

TABLE 21 I-0103

404 1.4 [3] a I-0104

363 1.3 [3] a I-0105

363 1.41 [3] a I-0106

361 1.51 [3] a I-0107

376 1.39 [1] a

TABLE 22 I-0108

420 1.65 [1] b I-0109

394 1.54 [1] a I-0110

363 1.3 [3] b I-0111

376.3 1.39 [1] b I-0112

381 1 [1] a

TABLE 23 I-0113

382 1.36 [1] a I-0114

385 1.09 [1] a I-0115

385 1.06 [1] a I-0116

430 1.46 [1] a I-0117

397 1.34 [1] a

TABLE 24 I-0118

427 1.39 [1] a I-0119

383 1.31 [1] a I-0120

367 0.93 [1] a I-0121

412 1.35 [1] b I-0122

400 1.5 [1] b

TABLE 25 I-0123

403 1.14 [1] b I-0124

400 1.58 [1] b I-0125

400 1.52 [1] b I-0126

430 1.44 [1] b I-0127

401 1.41 [1] b

TABLE 26 I-0128

403 1.51 [1] a I-0129

382 1.49 [1] b I-0130

382 1.43 [1] b I-0131

400 1.59 [1] b I-0132

430 1.44 [1] b

TABLE 27 I-0133

431 1.47 [1] b I-0134

403 1.67 [1] b I-0135

418 1.59 [1] b I-0136

417 1.67 [1] b I-0137

418 1.59 [1] b

TABLE 28 I-0138

426.3 1.24 [1] b I-0139

396 1.53 [1] b I-0140

396 1.47 [1] b I-0141

421 1.63 [1] b I-0142

418 1.56 [1] b

TABLE 29 I-0143

419.2 1.35 [1] b I-0144

401.2 1.22 [1] b I-0145

413.2 1.63 [1] b I-0146

395.3 1.51 [1] b I-0147

436.2 1.56 [1] b

TABLE 30 I-0148

418 1.48 [1] b I-0149

436.2 1.6 [1] b I-0150

400.3 1.35 [1] b I-0151

400.2 1.32 [1] b

TABLE 31 Reten- Compound tion time LC/MS Optical No. Chemical structure[M + H] (min) condition activity I-0152

429 1.55 [1] a I-0153

434 1.71 [1] a I-0154

433.3 1.54 [1] b I-0155

415.3 1.42 [1] b I-0156

459.2 1.53 [1] b

TABLE 32 I-0157

450.2 1.73 [1] b I-0158

462.2 1.55 [1] b I-0159

433 1.57 [1] b I-0160

400 1.33 [3] b I-0161

418 1.39 [3] b

TABLE 33 I-0162

437 1.63 [1] b I-0163

422 1.41 [3] a I-0164

430 1.42 [1] b I-0165

447 1.68 [1] b I-0166

421 1.78 [1] a

TABLE 34 I-0167

449 1.56 [1] a I-0168

436 1.35 [1] b I-0169

422.3 1.24 [1] a I-0170

406 1.54 [1] a I-0171

448 1.32 [1] b

TABLE 35 I-0172

466 1.4 [1] b I-0173

376 1.89 [1] c I-0174

376 1.61 [1] c I-0175

419 0.96 [1] b I-0176

432 1.41 [1] b

TABLE 36 I-0177

362 1.42 [1] a I-0178

404 1.61 [1] a I-0179

378 1.15 [1] a I-0180

418 1.74 [1] a I-0181

446 1.43 [1] b

TABLE 37 I-0182

449 1.31 [1] b I-0183

392 1.28 [1] a I-0184

482 1.49 [1] b I-0185

488 1.5 [1] b I-0186

488 1.51 [1] b

TABLE 38 I-0187

472 1.36 [1] b I-0188

388 1.36 [1] b I-0189

443 1.74 [2] b I-0190

488 1.48 [1] b

TABLE 39 I-0191

416 1.67 [2] b I-0192

454 1.8 [1] b I-0193

481 1.78 [1] b I-0194

432 1.34 [1] b I-0195

401 1.11 [1] b

TABLE 40 I-0196

406 1.36 [1] a I-0197

406 1.38 [1] a I-0198

406 1.37 [1] a I-0199

510 1.41 [1] b I-0200

443 1.54 [1] b

TABLE 41 I-0201

432 1.53 [1] b I-0202

446 1.56 [1] b

TABLE 42 Retention Compound time LC/MS Optical No. Chemical structure[M + H] (min) condition activity I-0203

498 1.79 [1] b I-0204

484 1.52 [1] b I-0205

482 1.73 [1] b I-0206

468 1.48 [1] b

TABLE 43 I-0207

432 1.45 [1] c I-0208

413 1.67 [1] b I-0209

443 1.75 [1] b I-0210

417 1.65 [1] b I-0211

431 1.74 [1] b

TABLE 44 I-0212

431 1.86 [1] b I-0213

457 1.25 [1] b I-0214

475 1.66 [2] b

TABLE 45 Compound No. NMR I-0059 1H-NMR (CDCl3) δ: 0.92 (t, J = 7.4 Hz,3H), 2.10-2.18 (m, 3H), 2.64-2.75 (m, 1H), 2.93-3.11 (m, 2H), 3.87 (s,3H), 5.43 (s, 1H), 5.58 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H),6.73-6.79 (m, 3H), 6.91 (d, J = 8.5 Hz, 1H), 7.30 (brs, 1H). I-01021H-NMR (DMSO-d₆) δ: 1.79 (s, 3H), 2.13 (m, 1H), 2.79 (m, 1H), 3.08 (m,2H), 4.94 (s, 4H), 5.85 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 7.6 Hz, 2H),7.00 (s, 1H), 7.11 (s, 1H), 7.25 (t, J = 9.2 Hz, 1H), 8.35 (s, 1H).I-0145 1H-NMR (CDCl3) δ: 1.79 (s, 3H), 3.36 (s, 3H), 3.84 (dd, J = 14.4,5.9 Hz, 1H), 4.45 (dd, J = 14.4, 10.4 Hz, 1H), 5.35 (dd, J = 10.3, 5.8Hz, 1H), 6.92 (s, 1H), 6.99 (t, J = 7.0 Hz, 2H), 7.22-7.29 (m, 2H).I-0147 1H-NMR (DMSO-d₆) δ: 1.65 (s, 3H), 3.01 (m, 1H), 3.16 (s, 3H),3.77(s, 3H), 4.24- 4.36 (m, 2H), 5.51 (bs, 1H), 6.83-6.98 (m, 1H),7.33-7.45 (m, 3H) I-0161 1H-NMR (CDCl3) δ: 1.74 (s, 3H), 3.39 (s, 3H),3.82 (dd, J = 14.2, 5.8 Hz, 1H), 4.43 (dd, J = 14.2, 10.4 Hz, 1H), 4.57(s, 2H), 5.37 (dd, J = 10.2, 5.8 Hz, 1H), 6.65 (s, 1H), 6.94-7.02 (m,3H), 7.11(d, J = 7.8 Hz, 1H) I-0162 1H-NMR (CDCl3) δ: 1.87 (s, 3H), 3.33(s, 3H), 3.82 (dd, J = 14.4, 5.6 Hz, 1H), 3.95 (s, 3H), 4.42 (dd, J =14.4, 10.4 Hz, 1H), 5.34 (dd, J = 10.3, 5.8 Hz, 1H), 6.71 (d, J = 10.3Hz, 1H), 6.98 (t, J = 7.0 Hz, 2H). I-0164 1H-NMR (CDCl3) δ: 1.74 (s,3H), 3.40 (s, 3H), 3.83 (dd, J = 14.3, 5.8 Hz, 1H), 4.44 (dd, J = 14.3,10.3 Hz, 1H), 5.01 (s, 4H), 5.38 (dd, J = 10.0, 5.8 Hz, 1H), 6.50 (s,1H), 6.99-7.02 (m, 3H). I-0168 1H-NMR (CDCl3) δ: 1.72 (s, 3H), 3.39 (s,3H), 3.82 (dd, J = 14.3, 6.0 Hz, 1H), 4.43 (dd, J = 14.3, 10.5 Hz, 1H),4.63 (s, 2H), 5.36 (dd, J = 10.3, 6.0 Hz, 1H), 6.68 (d, J = 7.0 Hz, 1H),6.83 (d, J = 10.5 Hz, 1H), 6.99 (t, J = 7.0 Hz, 2H), 7.24 (brs, 1H)I-0171 1H-NMR (CDCl3) δ: 1.67 (s, 3H), 2.05 (t, J = 5.8 Hz, 1H), 3.39(s, 3H), 3.82 (dd, J = 14.3, 5.8 Hz, 1H), 3.92 (m, 2H), 4.00 (m, 2H),4.43 (dd, J = 14.3, 10.3 Hz, 1H), 5.37 (dd, J = 10.3, 5.8 Hz, 1H), 6.23(d, J = 2.3 Hz, 1H), 6.55 (dd, J = 8.3, 2.3 Hz, 1H), 7.01 (m, 3H), 7.12(s, 1H). I-0176 1H-NMR (CDCl3) δ: 0.83 (t, J = 7.5 Hz, 3H), 2.04 (q, J =7.5 Hz, 2H), 3.40 (s, 3H), 3.81 (dd, J = 14.3, 6.0 Hz, 1H), 4.43 (dd, J= 14.3, 10.3 Hz, 1H), 4.58 (s, 2H), 5.36 (dd, J = 10.3, 6.0 Hz, 1H),6.67 (s, 1H), 6.98-7.02 (m, 3H), 7.12 (d, J = 7.8 Hz, 1H). I-0188 1H-NMR(CDCl3) δ: 3.37 (s, 3H), 3.73 (dd, J = 13.9, 5.8 Hz, 1H), 4.37-4.44 (m,2H), 4.55-4.62 (m, 2H), 5.14 (dd, J = 10.2, 5.8 Hz, 1H), 6.91-7.00 (m,4H), 7.24-7.28 (m, 3H).

TABLE 46 I-0192 1H-NMR (CDCl3) δ: 1.71 (s, 3H), 3.39 (s, 3H), 3.83 (dd,J = 14.4, 5.8 Hz, 1H), 4.44 (dd, J = 14.4, 10.4 Hz, 1H), 5.36 (dd, J =10.4, 5.8 Hz, 1H), 6.44 (t, J = 74.0 Hz, 2H), 6.75 (dd, J = 8.2, 2.2 Hz,1H), 6.95-7.03 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H). I-0201 1H-NMR (CDCl3)δ: 1.74 (s, 3H), 3.36 (s, 3H), 3.40 (s, 3H), 3.82 (dd, J = 14.3, 5.8 Hz,1H), 4.35 (s, 2H), 4.43 (dd, J = 14.3, 10.5 Hz, 1H), 5.37 (dd, J = 10.4,5.9 Hz, 1H), 6.62 (s, 1H), 6.95-7.00 (m, 3H), 7.11(d, J = 7.8 Hz, 1H)

Biological test examples for the compounds of the present invention aredescribed below.

The compounds represented by Formula (I) according to the presentinvention needs only to have an antagonistic activity for the P2X₇receptor so as to inhibit the human P2X₇ receptor.

Specifically, in the evaluation methods described below, IC50 ispreferably 5000 nM or less, more preferably 1000 nM or less, furtherpreferably 100 nM or less.

Evaluation of a human P2X₇ receptor inhibitory activity Stablyexpressing cell line (1321N1 cell transfected with the human P2X₇receptor gene (GenBank accession number NM_002562.5 including T606C andG952A SNP)) was used. The cells were seeded in a 384-well microtiterplate at a concentration of 8000 cells/well and cultured in the medium(10% fetal bovine serum, 25 mM HEPES, 1% penicillin and streptomycin inDMEM) for one day at 37° C. under 5% carbon dioxide atmosphere. Afterreplacing with 20 μL of the HBSS buffer (20 mM HEPES, 55.6 mM D-glucose,1× HBSS(−), pH7.4-7.5), 15 μL of 17.3 μM Yo-Pro solution in the HBSSbuffer was added. The plate was placed in high-throughput cellularscreening system FLIPR TETRA (Molecullar Devices, LLC.) and 15 μL of 130μM BzATP solution in the HBSS buffer was added. Measurement offluorescence intensity by FLIPR TETRA was started. After eight minutes,15 μL of DMSO solutions containing different concentrations of thecompound of the present invention as prepared by dilution with the HBSSbuffer were dispensed to each well through the built-in automaticdispenser, and the measurement of fluorescence intensity was continuedfor 20 minutes. The maximum fluorescence intensity without the compoundof the present invention is calculated as 0% inhibition and the maximumfluorescence intensity when the reference compound was added iscalculated as 100% inhibition. Changing values of fluorescence intensityby the compound of the present invention were calculated by differencebetween maximum and minimum fluorescence intensity for 20 minutes.Inhibition ratios (%) were calculated from the following equation:

Inhibition Ratio:

$\left\lbrack {1 - \frac{\begin{matrix}{{{changing}\mspace{14mu}{values}\mspace{14mu}{by}\mspace{14mu} a\mspace{14mu}{compound}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{present}\mspace{14mu}{invention}} -} \\{{changing}\mspace{14mu}{values}\mspace{14mu}{by}\mspace{14mu}{reference}\mspace{14mu}{compound}}\end{matrix}}{\begin{matrix}{{{changing}\mspace{14mu}{values}\mspace{14mu}{without}\mspace{14mu} a\mspace{14mu}{compound}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{present}\mspace{14mu}{invention}} -} \\{{changing}\mspace{14mu}{values}\mspace{14mu}{by}\mspace{14mu}{reference}\mspace{14mu}{compound}}\end{matrix}}} \right\rbrack \times 100\mspace{14mu}(\%)$IC₅₀ was calculated using logistic approximation.

The antagonistic activity for the human P2X₇ receptor of the compoundsof the present invention is shown in the following table.

TABLE 47 Compound No. IC50 (nM) I-0001 16 I-0003 1.8 I-0004 37 I-0009 22I-0032 16 I-0059 11 I-0069 10 I-0091 17 I-0100 12 I-0102 11 I-0106 11I-0107 25 I-0145 19 I-0147 24 I-0149 21 I-0150 18 I-0151 14

TABLE 48 Compound No. IC50(nM) I-0154 17 I-0158 27 I-0161 19 I-0162 19I-0164 28 I-0168 23 I-0171 19 I-0176 20 I-0188 7.6 I-0192 18 I-0201 26

The antagonistic activity for the human P2X₇ receptor of the othercompounds of the present invention is shown in the following table. Asfor IC₅₀ value, value to below 10 nmol/L is represented as “A”, valuefrom 10 nmol/L to below 100 nmol/L is represented as “B”, value from 100nmol/L to below 500 nmol/L is represented as “C”, and value from 500nmol/L to below 1 μmol/L is represented as “D”.

TABLE 49 Compound No. IC50 I-0002 A I-0005 B I-0006 B I-0007 A I-0008 AI-0010 A I-0011 A I-0012 A I-0013 A I-0014 A I-0015 B I-0016 B I-0017 BI-0018 B I-0019 A I-0020 A I-0021 B I-0022 A I-0023 A I-0024 B I-0025 BI-0026 A I-0027 A I-0028 A I-0029 A I-0030 C I-0031 B I-0033 B I-0034 BI-0035 C I-0036 B I-0037 A I-0038 A I-0039 A I-0040 B I-0041 A I-0042 AI-0043 A I-0044 B I-0045 B I-0046 B I-0047 B I-0048 B I-0049 A I-0050 AI-0051 B I-0052 B I-0053 B I-0054 A I-0055 B I-0056 B I-0057 B I-0058 AI-0059 B I-0060 B I-0061 B I-0062 B I-0063 B I-0064 B I-0065 A I-0066 AI-0067 A I-0068 B I-0070 B I-0071 B I-0072 B I-0073 B I-0074 A I-0075 BI-0076 B I-0077 A I-0078 B I-0079 B I-0080 A I-0081 B I-0082 B I-0083 BI-0084 B I-0085 B I-0086 B I-0087 B I-0088 D I-0089 B I-0090 B I-0092 BI-0093 C I-0094 B I-0095 B I-0096 B I-0097 A I-0098 A I-0099 A I-0101 BI-0103 B I-0104 B I-0105 B I-0108 B I-0109 B I-0110 A I-0111 A I-0112 DI-0113 D I-0114 C I-0115 C I-0116 C I-0117 C I-0118 C I-0119 B I-0120 CI-0121 B I-0122 B I-0123 B I-0124 B I-0125 B I-0126 B I-0127 B I-0128 BI-0129 B I-0130 B I-0131 B I-0132 B I-0133 B I-0134 A I-0135 B I-0136 BI-0137 B I-0138 B I-0139 B I-0140 B I-0141 B I-0142 B I-0143 B I-0144 BI-0145 B I-0146 B I-0147 B I-0148 B

TABLE 50 Compound No. IC50 I-0152 B I-0153 B I-0155 B I-0156 B I-0157 BI-0159 B I-0160 B I-0163 B I-0165 B I-0166 B I-0167 C I-0169 B I-0170 BI-0172 B I-0173 D I-0174 C I-0175 B I-0177 C I-0178 B I-0179 C I-0180 BI-0181 B I-0182 B I-0183 C I-0184 B I-0185 B I-0186 B I-0187 B I-0189 BI-0190 B I-0191 B I-0193 B I-0194 B I-0195 B I-0196 B I-0197 B I-0198 BI-0199 B I-0200 B I-0202 B

TABLE 51 Compound No. IC50 I-0203 B I-0204 B I-0205 B I-0206 B I-0207 CI-0208 B I-0209 B I-0210 B I-0211 B I-0212 B I-0213 B I-0214 B

Test Example 2 Evaluation of the Rat P2X₇ Receptor Inhibitory Activity

Stably expressing cell line (1321N1 cell transfected with the rat P2X₇receptor gene (GenBank accession number NM_019256.1 including C586T andC652A SNP)) is used. The cells are seeded in a 384-well microtiter plateat a concentration of 10000 cells/well and cultured in the medium (10%fetal bovine serum, 2 mM ClutaMax-1, 1% penicillin and streptomycin inDMEM) for one day at 37° C. under 5% carbon dioxide atmosphere. Afterreplacing with 20 μL of the HBSS buffer (20 mM HEPES, 55.6 mM D-glucose,1× HBSS(+), pH7.4), 15 μL of 17.3 μM Yo-Pro solution in the HBSS bufferis added. The plate is placed in high-throughput cellular screeningsystem FLIPR TETRA (Molecullar Devices, LLC.) and 15 μL of 1083 μM BzATPsolution in the HBSS buffer is added. Measurement of fluorescenceintensity by FLIPR TETRA is started. Eight minutes after, 15 μL of DMSOsolutions containing different concentrations of the compound of thepresent invention as prepared by dilution with the HBSS buffer aredispensed to each well through the built-in automatic dispenser, and themeasurement of fluorescence intensity is continued for 20 minutes. Themaximum fluorescence intensity without the compound of the presentinvention is calculated as 0% inhibition and the maximum fluorescenceintensity when the reference compound is added is calculated as 100%inhibition. Changing values of fluorescence intensity by the compound ofthe present invention are calculated by difference between maximum andminimum fluorescence intensity for 20 minutes. Inhibition ratios (%) arecalculated from the following equation:

Inhibition Ratio:

$\left\lbrack {1 - \frac{\begin{matrix}{{{changing}\mspace{14mu}{values}\mspace{14mu}{by}\mspace{14mu} a\mspace{14mu}{compound}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{present}\mspace{14mu}{invention}} -} \\{{changing}\mspace{14mu}{values}\mspace{14mu}{by}\mspace{14mu}{reference}\mspace{14mu}{compound}}\end{matrix}}{\begin{matrix}{{{changing}\mspace{14mu}{values}\mspace{14mu}{without}\mspace{14mu} a\mspace{14mu}{compound}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{present}\mspace{14mu}{invention}} -} \\{{changing}\mspace{14mu}{values}\mspace{14mu}{by}\mspace{14mu}{reference}\mspace{14mu}{compound}}\end{matrix}}} \right\rbrack \times 100\mspace{14mu}(\%)$

IC₅₀ is Calculated Using Logistic Approximation.

Test Example 3-1 Analgesic Effect in a Seltzer Model

Preparation of Partial Sciatic Nerve Ligation Model in Rats

Rats were anaesthetized using isoflurane/O2 inhalation anaesthesia.After induction of anesthesia, the left thigh was shaved. An incisionwas made in the skin just below the hip bone. The muscle was bluntlydissected to expose the sciatic nerve. About one half (½) of the sciaticnerve thickness was tightly ligated with a nylon thread and the woundwas closed. The right thigh was used as a sham-operated control. Theright thigh underwent an identical procedure with the left hind limb,however, the sciatic nerve was not manipulated or ligated.

Evaluation (1)

Two weeks after nerve ligation, the effect on mechanical allodynia wasassessed using a series of von Frey filaments. For habituation, the ratswere placed into a plastic cage on a wire mesh bottom. Von Freyfilaments (0.4 to 26 g) were applied to the plantar surface of the rathind paws from the wire mesh side, and the value of the filamentpressure at which the paw was withdrawn was used as a pain threshold.The measurement of mechanical sensitivity of the right and left hindpaws was performed to obtain predose mechanical sensitivity. The ratsshowing the threshold change from 0.6 to 2 g (in nerve ligated side) and8 to 15 g (in sham operated side) were used in the experiments. On theday before the experiment, the rats were evaluated with a series of vonFrey filaments to familiarize them with the test procedure. The adoptedanimal was administrated with the compounds of the present invention.The compounds of the present invention were homogenized with mortar andpestle and suspended or diluted in 0.5% Methyl Cellulose to prepare0.03-100 mg/2 mL/kg suspension and orally administered to rat using asyringe attached with a sonde. Post-dose mechanical sensitivities of theright and left hind paws were measured at approximately 1 to 5 hoursafter drug administration. Percent reversal of mechanical allodynia foreach rat was calculated using the following formula. The analgesiceffects of the compounds were compared.

${\%\mspace{14mu}{Reversal}} = {100 \times \frac{\begin{matrix}{{{Log}_{10}\left( {{Postdose}\mspace{14mu}{mechanical}\mspace{14mu}{sensitivity}\mspace{14mu}{in}\mspace{14mu}{nerve}\mspace{14mu}{ligated}\mspace{14mu}{side}} \right)} -} \\{{Log}_{10}\left( {{Predose}\mspace{14mu}{mechanical}\mspace{14mu}{sensitivity}\mspace{14mu}{in}\mspace{14mu}{nerve}\mspace{14mu}{ligated}\mspace{14mu}{side}} \right)}\end{matrix}}{\begin{matrix}{{{Log}_{10}\left( {{Predose}\mspace{14mu}{mechanical}\mspace{14mu}{sensitivity}\mspace{14mu}{in}\mspace{14mu}{sham}\mspace{14mu}{operated}\mspace{14mu}{side}} \right)} -} \\{{Log}_{10}\left( {{Predose}\mspace{14mu}{mechanical}\mspace{14mu}{sensitivity}\mspace{14mu}{in}\mspace{14mu}{nerve}\mspace{14mu}{ligated}\mspace{14mu}{side}} \right)}\end{matrix}}}$Results

TABLE 52 Compound No. % reversal I-0102 55% (3 mg/kg) I-0135 52% (3mg/kg) I-0145 58% (1 mg/kg) I-0147 33% (1 mg/kg) I-0149 41% (1 mg/kg)I-0154 44% (1 mg/kg) I-0158 47% (1 mg/kg) I-0161 51% (1 mg/kg) I-016447% (1 mg/kg) I-0168 53% (1 mg/kg) I-0171 52% (1 mg/kg) I-0192 50% (1mg/kg) I-0201 51% (1 mg/kg)Evaluation (2)

Mechanical hyperalgesia is evaluated using an analgesy meter (RandallSelitto). Two weeks after nerve ligation, the paw pressure test isperformed using an analgesy meter (stimulus pressure increased 16 g persecond) to obtain paw withdrawal thresholds (PWT). Measurements are madeon both sides of the hind paw and to obtain pre-dose PWT. The ratsshowing the threshold change from 60 to 90 g (in nerve ligated side) and100 to 175 g (in sham operated side) are used in the experiments. On theday before the experiment, the rats have their hind paws set on theapparatus to familiarize them with the test procedure. The adoptedanimal is administrated with the compound of the present invention. Thecompounds of the present invention are homogenized with mortar andpestle and suspended or diluted in 0.5% Methyl Cellulose to prepare0.03-100 mg/2 mL/kg suspension and orally administered to rat using asyringe attached with a sonde. Post-dose PWT of the right and left hindpaws are measured at approximately 1 to 5 hours after drugadministration. Percent reversal of mechanical hyperalgesia for each ratis calculated using the following formula. The analgesic effects of thecompounds are compared.

${\%\mspace{14mu}{Reversal}} = {100 \times \frac{\begin{matrix}{{{Postdose}\mspace{14mu}{PWT}\mspace{14mu}{in}\mspace{14mu}{nerve}\mspace{14mu}{ligated}\mspace{14mu}{side}} -} \\{{Predose}\mspace{14mu}{PWT}\mspace{14mu}{in}\mspace{14mu}{nerve}\mspace{14mu}{ligated}\mspace{14mu}{side}}\end{matrix}}{\begin{matrix}{{{Predose}\mspace{14mu}{PWT}\mspace{14mu}{in}\mspace{14mu}{sham}\mspace{14mu}{operated}\mspace{14mu}{side}} -} \\{{Predose}\mspace{14mu}{PWT}\mspace{14mu}{in}\mspace{14mu}{nerve}\mspace{14mu}{ligated}\mspace{14mu}{side}}\end{matrix}}}$

Test Example 3-2 Analgesic Effect in a Cauda Equina Nerve CompressionModel

Preparation of Animal Model

In order to prepare animal models, an incision is made in the lumbarportions of the back of rats under anesthesia to expose the fourth,fifth, and sixth lumbar vertebras. An incision is made in the 4-5 and5-6 lumbar vertebral joints. Silicon rubber is inserted into the fourthand sixth lumbar vertebral canals from the wounds of the vertebraljoints, and indwelled. The wounds are closed.

In order to sham-operated animals, rats are operated by the aboveprocedures except for the insertion and indwelling of silicon rubber.

Evaluation of Analgesic Effect

Two weeks after operation, the effect on mechanical allodynia isassessed using a series of von Frey filaments. For habituation, the ratsare placed into a plastic cage on a wire mesh bottom. Von Frey filaments(0.4 to 26 g) were applied to the plantar surface of the rat hind pawsfrom the wire mesh side, and the value of the filament pressure at whichthe paw was withdrawn was used as a pain threshold. The measurement ofmechanical sensitivity of the right and left hind paws is performed toobtain predose mechanical sensitivity. The mechanical sensitivity ofboth hind paws is evaluated to obtain predose mechanical sensitivity inthe animal models showing the threshold change from 0.4 to 1 g and ahigher pain threshold. The rats showing the threshold change from 8 to15 g (in sham-operated group) are used in the experiments. On the daybefore the experiment, the rats are evaluated with a series of von Freyfilaments to familiarize them with the test procedure. The adoptedanimal is administrated with the compounds of the present invention. Thecompounds of the present invention are homogenized with mortar andpestle and suspended or diluted in 0.5% Methyl Cellulose to prepare0.03-100 mg/2 mL/kg suspension and orally administered to rat using asyringe attached with a sonde. Post-dose mechanical sensitivities of theright and left hind paws are measured at approximately 1 to 5 hoursafter drug administration. Percent reversal of mechanical allodynia foreach rat is calculated using the following formula. The analgesiceffects of the compounds are compared.

Test Example 3-3 Analgesic Effect in an EAE Model

Preparation of Rat Experimental Autoimmune Encephalomyelitis Model

Rats (Lewis rats, female) are anaesthetized using isoflurane. The backsat the tail bases are shaved. 1 g/L of an emulsion containing CFA(complete Freund's adjuvant) and the saline solution of MBP (myelinbasic protein) mixed at 1:1 is prepared, and subcutaneously administeredat 100 uL/animal to the backs at the rat tail bases for immunization.This is used as an operated group. An emulsion with CFA is preparedusing MBP-free saline, and similar treatment is performed. This is usedas a sham-operated group.

Evaluation

Three weeks after immunization, the effect on mechanical allodynia isassessed using a series of von Frey filaments. For habituation, the ratsare placed into a plastic cage on a wire mesh bottom. Von Frey filaments(0.4 to 26 g) were applied to the plantar surface of the rat hind pawsfrom the wire mesh side, and the value of the filament pressure at whichthe paw was withdrawn was used as a pain threshold. The mechanicalsensitivity of both hind paws is evaluated to obtain predose mechanicalsensitivity in the animal models showing the threshold change from 4 gor less and a higher pain threshold from 0.6 to 2 g. The rats showingthe threshold change from 6 to 15 g (in sham-operated group) are used inthe experiments. On the day before the experiment, the rats areevaluated with a series of von Frey filaments to familiarize them withthe test procedure. The adopted animal is administrated with thecompounds of the present invention. The compounds of the presentinvention are homogenized with mortar and pestle and suspended ordiluted in 0.5% Methyl Cellulose to prepare 0.03-100 mg/2 mL/kgsuspension and orally administered to rat using a syringe attached witha sonde. Post-dose mechanical sensitivities of the hind paws aremeasured at approximately 1 to 5 hours after drug administration.Percent reversal of mechanical allodynia for each rat is calculatedusing the following formula. The analgesic effects of the compounds arecompared. % Reversal=Log₁₀ (Postdose mechanical sensitivity in theoperated group)−Log₁₀ (Predose mechanical sensitivity in the operatedgroup)/Log₁₀ (Predose mechanical sensitivity in the sham-operatedgroup)−Log₁₀ (Predose mechanical sensitivity in the operated group)

The antagonistic activity for the P2X₇ receptor of the compounds of thepresent invention can be also evaluated by using the method described inBritish Journal of Pharmacology (2013) 170 624-640.

Test Example 4 CYP Inhibition Test

Using commercially available pooled human liver microsomes, aninhibitory degree of each metabolite production amount by the compoundof the present invention is assessed as marker reactions of human mainfive CYP isoforms (CYP1A2, 2C9, 2C19, 2D6, and 3A4), 7-ethoxyresorufin0-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9),mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation(CYP2D6), and terfenedine hydroxylation (CYP3A4).

The reaction conditions are as follows: substrate, 0.5 μmol/Lethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/LS-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/Lterfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature,37° C.; enzyme, pooled human liver microsomes 0.2 mg protein/mL;concentration of the compound of the present invention, 1.0, 5.0, 10, 20μmol/L (four points).

Each five kinds of substrates, human liver microsomes, or the compoundof the present invention in 50 mmol/L Hepes buffer are added to a96-well plate at the composition as described above, and NADPH, as acofactor is added to initiate metabolism reactions. After the incubationat 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (V/V) solution isadded to stop the reaction. After the centrifugation at 3000 rpm for 15minutes, resorufin (CYP1A2 metabolite) in the supernatant is quantifiedby a fluorescent multilabel counter or LC/MS/MS and hydroxytolbutamide(CYP2C9 metabolite), 4′ hydroxymephenytoin (CYP2C19 metabolite),dextrorphan (CYP2D6 metabolite), and terfenadine alcohol metabolite(CYP3A4 metabolite) are quantified by LC/MS/MS.

The sample obtained by adding only DMSO that is a solvent dissolving acompound instead of the compound of the present invention to a reactionmixture is adopted as a control (100%). Remaining activity (%) iscalculated at each concentration of the compound of the presentinvention compared to control, and IC₅₀ is calculated by reversepresumption by a logistic model using a concentration and an inhibitionrate.

Test Example 5 CYP3A4 (MDZ) MBI Test

The CYP3A4 (MDZ) MBI test is a test of investigating Mechanism basedinhibition (MBI) potential on CYP3A4 inhibition of the compound of thepresent invention by the enhancement of the inhibitory effect caused bya metabolic reaction of the compound of the present invention. CYP3A4inhibition is evaluated using pooled human liver microsomes by1-hydroxylation reaction of midazolam (MDZ) as a marker reaction.

The reaction conditions are as follows: substrate, 10 μmol/L MDZ;pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2minutes; reaction temperature, 37° C.; protein content of pooled humanliver microsomes, at pre-reaction 0.5 mg/mL, at reaction 0.05 mg/mL (at10-fold dilution); concentrations of the compound of the presentinvention, 1, 5, 10, 20 μmol/L (four points).

Pooled human liver microsomes and a solution of the compound of thepresent invention in K-Pi buffer (pH 7.4) as a pre-reaction solution areadded to a 96-well plate at the composition of the pre-reaction. A partof pre-reaction solution is transferred to another 96-well plate, and1/10 diluted by K-Pi buffer containing a substrate. NADPH as a cofactoris added to initiate a reaction as a marker reaction (Preincubation 0min). After a predetermined time of a marker reaction, a solution ofmethanol/acetonitrile=1/1 (V/V) is added to stop the reaction. Inaddition, NADPH is added to a remaining pre-reaction solution toinitiate a pre-reaction (Preincubation 30 min). After a predeterminedtime of a pre-reaction, a part is transferred to another 96-well plate,and 1/10 diluted by K-Pi buffer containing a substrate to initiate areaction as a marker reaction. After a predetermined time of a markerreaction, a solution of methanol/acetonitrile=1/1 (V/V) is added to stopthe reaction. After centrifuged at 3000 rpm for 15 minutes,1-hydroxymidazolam in the supernatant is quantified by LC/MS/MS.

The sample obtained by adding only DMSO that is a solvent dissolving acompound instead of the compound of the present invention to a reactionmixture is adopted as a control (100%). Remaining activity (%) iscalculated at each concentration of the compound of the presentinvention compared to control, and IC value is calculated byreverse-presumption by a logistic model using a concentration and aninhibition rate. Shifted IC value is calculated as “IC of preincubation0 min/IC of preincubation 30 min”. When a shifted IC is 1.5 or more,this is defined as positive. When a shifted IC is 1.0 or less, this isdefined as negative.

Test Example 6 BA Test

Materials and Methods for Experiments to Evaluate Oral Absorption

-   (1) Animals: The mice or rats are used-   (2) Breeding conditions: The mice or rats are allowed to freely take    solid food and sterilized tap water.-   (3) Dose and grouping: orally or intravenously administered at a    predetermined dose; grouping is as follows (Dose depends on the    compound)-   Oral administration: 2 to 60 μmol/kg or 1 to 30 mg/kg (n=2 to 3)    Intravenous administration: 1 to 30 μmol/kg or 0.5 to 10 mg/kg (n=2    to 3)-   (4) Preparation of dosing solution: for oral administration, in a    solution or a suspension state; for intravenous administration, in a    solubilized state-   (5) Administration method: in oral administration, forcedly    administer into ventriculus with oral probe; in intravenous    administration, administer from caudal vein with a needle-equipped    syringe-   (6) Evaluation items: blood is collected over time, and the plasma    concentration of drug is measured by LC/MS/MS-   (7) Statistical analysis: regarding the transition of the plasma    concentration of the compound of the present invention, the area    under the plasma concentration-time curve (AUC) is calculated by    non-linear least squares program WinNonlin (Registered trade name),    and the bioavailability (BA) is calculated from the AUCs of the oral    administration group and intravenous administration group.

Test Example 7 Fluctuation Ames Test

Mutagenicity of the compound of the present invention is evaluated.

A 20 μL of freezing-stored Salmonella typhimurium (TA98 strain, TA100strain) is inoculated on 10 mL of a liquid nutrient medium (2.5% Oxoidnutrient broth No. 2), and this is incubated at 37° C. for 10 hoursunder shaking. The 7.70 to 8.00 mL of TA98 culture medium is centrifuged(2000×g, 10 minutes) Bacteria are suspended in a Micro F buffer (K₂HPO₄:3.5 g/L, KH₂PO₄: 1 g/L, (NH₄)₂SO₄: 1 g/L, trisodium citrate dihydrate:0.25 g/L, and MgSO₄.7H₂O: 0.1 g/L) with the same volume as that of theculture medium used for centrifugation. The suspension is added to 120mL of Exposure medium (Micro F buffer containing biotin: 8 μg/mL,histidine: 0.2 μg/mL, and glucose: 8 mg/mL). The 3.10 to 3.42 mL ofTA100 culture medium strain is mixed with 120 to 130 mL Exposure medium.Each 12 μL of DMSO solution of the compound of the present invention(several stage dilution from maximum dose 50 mg/mL at 2 to 3 foldratio), DMSO as a negative control, and 50 μg/mL of 4-nitroquinoline1-oxide DMSO solution for the TA98 strain and 0.25 μg/mL of2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100strain in the assay without metabolic activation, 40 μg/mL of2-aminoanthracene DMSO solution for the TA98 strain and 20 μg/mL of2-aminoanthracene DMSO solution for the TA100 strain in the assay withmetabolic activation as a positive control, and 588 μL of the testbacterial suspension (498 μL and 90 μL of S9 mixture in the case ofmetabolic activation assay) are mixed, and this is incubated at 37° C.for 90 minutes under shaking. A 460 μL of the mixture is mixed with 2300μL of Indicator medium (Micro F buffer containing 8 μg/mL biotin, 0.2μg/mL histidine, 8 mg/mL glucose, 37.5 μg/mL bromocresol purple), each50 μL is dispensed to microplate 48 wells/dose, and this is incubated at37° C. for 3 days. Since the wells containing the bacteria which gainedgrowth ability by point mutation in amino acid (histidine) synthesizingenzyme gene turns from purple to yellow due to a pH change, the numberof yellow wells in 48 wells is counted per dose, and is compared withthe negative control group. (−) and (+) means negative and positive inmutagenicity respectively.

Test Example 8 hERG Test

For the purpose of assessing risk of an electrocardiogram QT intervalprolongation of the compound of the present invention, effects of thecompound of the present invention on delayed rectifier K+ current(I_(Kr)), which plays an important role in the ventricularrepolarization process, is studied using CHO cells expressing humanether-a-go-go related gene (hERG) channel.

After a cell is retained at a membrane potential of −80 mV by whole cellpatch clamp method using an automated patch clamp system (QPatch;Sophion Bioscience A/S) and gave a leak potential of −50 mV, Ix, inducedby depolarization pulse stimulation at +20 mV for 2 seconds and,further, repolarization pulse stimulation at −50 mV for 2 seconds, isrecorded. Extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L,CaCl₂: 2 mmol/L, MgCl₂: 1 mmol/L, glucose: 10 mmol/L, HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4)adjusted to contain 0.1% dimethylsulfoxide is used as a medium. Theextracellular solution in which the medium and the compound of thepresent invention had been dissolved at each objective concentration isapplied to the cell for 7 minutes or more at room temperature. From therecording I_(Kr), an absolute value of the tail peak current is measuredbased on the current value at the resting membrane potential usinganalysis software (QPatch Assay software; Sophion Bioscience A/S).Further, the tail peak current after application of the compound of thepresent invention relative to the tail peak current after application ofthe medium is calculated as a inhibition to assess the influence of thecompound of the present invention on I_(Kr).

Test Example 9 Solubility Test

The solubility of the compound of the present invention is determinedunder 1% DMSO addition conditions. 10 mmol/L solution of the compound isprepared with DMSO. 2 μL of the solution of the compound of the presentinvention is respectively added to 198 μL of JP-1 fluid or JP-2 fluid.The mixture is left shaking at room temperature for 1 hour, and themixture is vacuum-filtered. The filtrate is 10- or 100-fold diluted withmethanol/water=1/1 (v/v) or acetonitrile/methanol/water=1/1/2 (v/v/v),and the compound concentration in the filtrate is measured with LC/MS orSolid-Phase Extraction (SPE)/MS by the absolute calibration method.

The composition of the JP-1 fluid is as below.

Water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloricacid to reach 1000 mL.

The composition of the JP-2 fluid is as below.

1 volume of water is added to 1 volume of the solution in which 3.40 gof potassium dihydrogen phosphate and 3.55 g of anhydrous disodiumhydrogen phosphate are dissolved in water to reach 1000 mL.

Test Example 10 Metabolism Stability Test

Using commercially available pooled human liver microsomes, the compoundof the present invention is reacted for a constant time, a remainingrate is calculated by comparing a reacted sample and an unreactedsample, thereby, a degree of metabolism in liver is assessed.

A reaction is performed (oxidative reaction) at 37° C. for 0 minute or30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/Lmagnesium chloride) containing 0.5 mg protein/mL of human livermicrosomes. After the reaction, 50 μL of the reaction solution is addedto 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at3000 rpm for 15 minutes. The compound of the present invention in thesupernatant is quantified by LC/MS/MS or Solid-Phase Extraction(SPE)/MS, and a remaining amount of the compound of the presentinvention after the reaction is calculated, letting a compound amount at0 minute reaction time to be 100%.

Test Example 11 Powder Solubility Test

Appropriate quantity of the compound of the present invention is put insuitable containers. 200 μL of JP-1 fluid (water is added to 2.0 g ofsodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), 200μL of JP-2 fluid (1 volume of water is added to 1 volume of the solutionwhich 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrousdisodium hydrogen phosphate dissolve in water to reach 1000 mL) or 20mmol/L sodium taurocholate (TCA)/JP-2 fluid (JP-2 fluid is added to 1.08g of TCA to reach 100 mL) is independently added to each container. Whentotal amount is dissolved after adding the test reagent, the compound ofthe present invention is added appropriately. After sealing and shakingat 37° C. for 1 hour, solution is filtrated and 100 μL of methanol isadded to 100 μL of each filtrate to dilute two-fold. The dilution rateis changed as necessary. After checking that there is no bubble andprecipitate, the container is sealed and shaken. The compound of thepresent invention is measured using HPLC by absolute calibration curvemethod.

Test Example 12 Brain Distribution Test

The compound of the present invention is intravenously administered at adose of 1 μmol/mL/kg or 0.5 mg/mL/kg to rats. After 30 minutes, the ratsare killed by exsanguination through whole blood collection from theinferior vena cava under isoflurane anesthesia.

Then, the brain is excised, and 20 to 25% homogenate is prepared withdistilled water.

The obtained blood is centrifuged, and plasma is then obtained. Then,control plasma and control brain are added to the brain sample and theplasma sample, respectively, at 1:1, and each sample is assayed usingLC/MS/MS. The measured area ratio (brain/plasma) obtained is used as abrain Kp value.

Test Example 13 P-gp Substrate Test

The compound of the present invention is added to one side of Transwell(registered trademark, CORNING) where human MDR1-expressing cells orparent cells have been monolayer-cultured. The cells are reacted for aconstant time. The membrane permeability coefficients from the apicalside toward the basolateral side (A→B) and from the basolateral sidetoward the apical side (B→A) are calculated for the MDR1-expressingcells or the parent cells, and the efflux ratio (ER; ratio of themembrane permeability coefficients of B→A and A→B) values of theMDR1-expressing cells and the parent cells are calculated. The effluxratio (ER) values of the MDR1-expressing cells and the parent cells arecompared to confirm whether or not the compound of the present inventionwould be a P-gp substrate.

Test Example 14 mdr1a (−/—) B6 Mouse P-gp Substrate Test

Animal Used

mdr1a (−/−) B6 Mice (Knockout Mice) or C57BL/6J Mice (Wild Mice)

Method

-   1. The mice are allowed to freely take solid food and sterilized tap    water.-   2. The compound of the present invention is administered to 3    animals at each point in time. Blood and brain samples are collected    at a predetermined point in time (e.g., 15 minutes, 30 minutes, 1    hour, 2 hours, 4 hours, 6 hours, 8 hours or 24 hours) after    administration. The blood (0.3-0.7 mL) is collected with a syringe    containing anticoagulants (EDTA and heparin). The blood and brain    samples are immediately cooled in ice.-   3. The blood sample is centrifugated (1780×g, 10 minutes) for    removal of cells to obtain plasma. Then, the plasma sample is    transferred to a tube, and stored at −70° C.-   4. The brain sample is homogenized at a tissue weight:distilled    water weight ratio=1:3, transferred to a tube, and stored at −70° C.-   5. The plasma and brain samples are deproteinized, and analyzed by    LC/MS/MS. A calibration curve prepared from blank plasma or blank    brain is used in measurement. A sample for quality control is used    to confirm measurement trueness and accuracy.-   6. Concentrations (ng/mL and ng/g) in the plasma and the brain are    analyzed by an appropriate method for determining pharmacokinetic    parameters, for example, WinNonlin (registered trademark)    pharmacokinetic analysis software program.    Analysis-   Kp; brain/plasma concentration ratio-   Kp ratio=knockout mouse (KO) Kp value/wild mouse (Wild) Kp value-   KO/Wild ratio of brain AUC/plasma AUC={brain AUC/plasma AUC    (KO)}/{brain AUC/plasma AUC (Wild)}

Test Example 15 Evaluation of Activation of Human Pregnane X Receptor(PXR)

A Human PXR activation (Puracyp, Inc.) kit was used for evaluation.

DPX2 cells expressing human PXR were seeded in a 96-well plate at aconcentration of 40000 cells/well and cultured at 37° C. under 5% carbondioxide for 24 hours (medium: culture medium for DPX2 cells containing10% fetal bovine serum, antibiotics, sodium pyruvate, D-glucose, andphenol red). After culture for 24 hours, a DMSO solution of the compoundof the present invention was diluted with a medium (dosing medium forDPX2 cells containing 10% fetal bovine serum, D-glucose, antibiotics,sodium pyruvate, and L-glutamine) so that the final concentration was 10and 50 μM, and a rifampicin DMSO solution as a positive control drug was0.2, 1, 2, and 20 μM. The medium was removed from the 96-well plateafter culture for 24 hours. 100 μL of the solution of the compound ofthe present invention and 100 μL of the rifampicin solution preparedwere added to each well, and cultured for 48 hours. The medium wasremoved from the 96-well plate after culture for 48 hours. 100 μL ofeach reaction mixture obtained by adding 5.25 μL of CellTiter-Fluor to10.5 mL of TubeE was filled therein. The plate was set in a plate reader(PerkinElmer, Inc.) after culture for 1 hour to measure the fluorescenceintensity at an interval of 0.1 seconds per well. The plate was takenout. 100 μL of a solution obtained by adding ONE-Glo Assay Substrate toONE-Glo Assaybuffer was added to each well. After 2 minutes from theaddition of the solution, the plate was set in the plate reader tomeasure the fluorescence intensity at an interval of 2 seconds per well.The PXR activity of the product of the present invention was a valueobtained by dividing the emission intensity by the fluorescenceintensity.

(Results)

TABLE 53 Compound No. PXR 10 μM PXR 50 μM I-0135 3 9 I-0142 5.8 13I-0145 1.9 6.2 I-0154 7.9 15.8 I-0158 1.2 4.7 I-0161 1.2 2.5 I-0162 6.720 I-0164 10.6 25 I-0168 0.9 1.7 I-0171 1.2 2.5 I-0176 1.1 2 I-0188 1.33.5 I-0192 7.9 15 I-0201 4 13.5

Formulation Example

The following Formulation Example s are only exemplified and notintended to limit the scope of the invention.

Formulation Example Formulation Example 1 Tablets

The compounds of the present invention, lactose and calcium stearate aremixed. The mixture is crushed, granulated and dried to give a suitablesize of granules. Next, calcium stearate is added to the granules, andthe mixture is compressed and molded to give tablets.

Formulation Example 2 Capsules

The compounds of the present invention, lactose and calcium stearate aremixed uniformly to obtain powder medicines in the form of powders orfine granules. The powder medicines are filled into capsule containersto give capsules.

Formulation Example 3 Granules

The compounds of the present invention, lactose and calcium stearate aremixed uniformly and the mixture is compressed and molded. Then, it iscrushed, granulated and sieved to give suitable sizes of granules.

Formulation Example 4 Orally Dispersing Tablets

The compounds of the present invention and crystalline cellulose aremixed, granulated and tablets are made to give orally dispersingtablets.

Formulation Example 5 Dry Syrups

The compounds of the present invention and lactose are mixed, crushed,granulated and sieved to give suitable sizes of dry syrups.

Formulation Example 6 Injections

The compounds of the present invention and phosphate buffer are mixed togive injections.

Formulation Example 7 Infusions

The compounds of the present invention and phosphate buffer are mixed togive infusions.

Formulation Example 8 Inhalations

The compound of the present invention and lactose are mixed and crushedfinely to give inhalations.

Formulation Example 9 Ointments

The compounds of the present invention and petrolatum are mixed to giveointments.

Formulation Example 10 Patches

The compounds of the present invention and base such as adhesive plasteror the like are mixed to give patches.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have an antagonistic activity forthe P2X₇ receptor and are considered to be useful as a therapeuticand/or preventive agent for diseases or conditions associated with theP2X₇ receptor.

The invention claimed is:
 1. A compound represented by Formula (I):

wherein Z¹ is N; Z² is C(R^(5a))(R^(5a′))_(or) N(R^(5b)); the dashedline represents the presence or absence of a bond; when the dashed linerepresents the presence of a bond, then R^(5a′) and R^(5b) are absent;R^(5a) is a hydrogen atom, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkyloxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkenylamino, substituted or unsubstituted alkynylamino, substituted orunsubstituted aromatic carbocyclyl, or substituted or unsubstitutedaromatic heterocyclyl; R^(5a′) is a hydrogen atom; R^(5b) is a hydrogenatom, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, or substituted or unsubstituted alkynyl; Ring Q is asubstituted or unsubstituted 5-membered non-aromatic heterocycle or asubstituted or unsubstituted 6-membered non-aromatic heterocycle; Y¹ isO; R^(2a) is a group represented by the formula:—(C(R^(2a′))(R^(2b′)))_(n)—R¹; R^(2b) is a hydrogen atom, halogen,hydroxy, substituted or unsubstituted alkyl, or substituted orunsubstituted alkyloxy; R^(2a′) is each independently a hydrogen atom,halogen, hydroxy, substituted or unsubstituted alkyl, or substituted orunsubstituted alkyloxy; R^(2b′) is each independently a hydrogen atom,halogen, hydroxy, substituted or unsubstituted alkyl, or substituted orunsubstituted alkyloxy; R^(a′) and R^(2b′) which are attached to thesame carbon atom may be taken together to form oxo; R¹ is substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutednon-aromatic carbocyclyl, substituted or unsubstituted aromaticheterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;X is N(R^(7a)); R^(7a) is a hydrogen atom, substituted or unsubstitutedalkyl, or substituted or unsubstituted alkylcarbonyl; R^(2c) is eachindependently a hydrogen atom, halogen, hydroxy, substituted orunsubstituted alkyl, or substituted or unsubstituted alkyloxy; R^(2d) iseach independently a hydrogen atom, halogen, hydroxy, substituted orunsubstituted alkyl, or substituted or unsubstituted alkyloxy; R^(2c)and R^(2d) which are attached to the same carbon atom may be takentogether to form a substituted or unsubstituted non-aromatic carbocycle,or two of R^(2c) may be taken together to form a substituted orunsubstituted non-aromatic carbocycle; R³ is substituted orunsubstituted aromatic carbocyclyl, substituted or unsubstitutedaromatic heterocyclyl, substituted or unsubstituted non-aromaticcarbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl;n is an integer from 0 to 4; and m is an integer from 0 to 4, or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 1, wherein R^(7a) is a hydrogen atom, or a pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 1, whereinR¹ is substituted or unsubstituted 6-membered aromatic carbocyclyl, orsubstituted or unsubstituted 5- to 6-membered aromatic heterocyclyl, ora pharmaceutically acceptable salt thereof.
 5. The compound according toclaim 1, wherein R¹ is 6-membered aromatic carbocyclyl substituted withone or more halogen atom(s) and optionally substituted with one or moreand same or different substituent(s), or 5- to 6-membered aromaticheterocyclyl substituted with one or more halogen atom(s) and optionallysubstituted with one or more and same or different substituent(s), or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1, wherein each of R^(2a′) and R^(2b′) is a hydrogen atom, or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1, wherein R^(2b) is a hydrogen atom, or a pharmaceuticallyacceptable salt thereof.
 8. The compound according to claim 1, whereinR³ is substituted or unsubstituted 6-membered aromatic carbocyclyl, orsubstituted or unsubstituted 6- to 10-membered aromatic heterocyclyl, ora pharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1, wherein n is 0, or a pharmaceutically acceptable salt thereof.10. The compound according to claim 1, wherein m is 0, or apharmaceutically acceptable salt thereof.
 11. The compound according toclaim 1, wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising the compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceutical additive.13. The pharmaceutical composition according to claim 12 having anantagonistic activity for the P2X₇ receptor.
 14. A method for inhibitingactivity of the P2X₇ receptor comprising administering an effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, to a patient.
 15. The compound according toclaim 1, wherein Ring Q is a substituted or unsubstituted 5-memberednon-aromatic heterocycle, or a pharmaceutically acceptable salt thereof.16. A method for treating pain, comprising administering an effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.
 17. The compoundaccording to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1, which is:

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising the compound according to claim 17, or apharmaceutically acceptable salt thereof, and a pharmaceutical additive.23. A method for treating pain, comprising administering an effectiveamount of the compound according to claim 17, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.
 24. Apharmaceutical composition comprising the compound according to claim18, or a pharmaceutically acceptable salt thereof, and a pharmaceuticaladditive.
 25. A method for treating pain, comprising administering aneffective amount of the compound according to claim 18, or apharmaceutically acceptable salt thereof, to a patient in need thereof.26. A pharmaceutical composition comprising the compound according toclaim 19, or a pharmaceutically acceptable salt thereof, and apharmaceutical additive.
 27. A method for treating pain, comprisingadministering an effective amount of the compound according to claim 19,or a pharmaceutically acceptable salt thereof, to a patient in needthereof.
 28. A pharmaceutical composition comprising the compoundaccording to claim 20, or a pharmaceutically acceptable salt thereof,and a pharmaceutical additive.
 29. A method for treating pain,comprising administering an effective amount of the compound accordingto claim 20, or a pharmaceutically acceptable salt thereof, to a patientin need thereof.
 30. A pharmaceutical composition comprising thecompound according to claim 21, or a pharmaceutically acceptable saltthereof, and a pharmaceutical additive.
 31. A method for treating pain,comprising administering an effective amount of the compound accordingto claim 21, or a pharmaceutically acceptable salt thereof, to a patientin need thereof.